Straightforward methodology for the enantioselective synthesis of benzo[a]- and indolo[2,3-a]quinolizidines

Article abstract of DOI:10.1021/jo070539g

(Chemical Equation Presented) An enantioselective two-step route to substituted benzo[a]- and indolo[2,3-a]quinolizidines has been developed. It consists of (i) a stereoselective cyclocondensation of a racemic or prochiral δ-oxo(di)ester with either (S)-(

Full text of DOI:10.1021/jo070539g

Straightforward Methodology for the Enantioselective Synthesis of
Benzo[a]- and Indolo[2,3-a]quinolizidines
Mercedes Amat,*,† Maria M. M. Santos,† Oriol Bassas,† Nu´ria Llor,† Carmen Escolano,†
Arantxa Go´mez-Esque´,† Elies Molins,‡ Steven M. Allin,§ Vickie McKee,§ and Joan Bosch*,†
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona, 08028-Barcelona, Spain,
Institut de Cie`ncia de Materials de Barcelona (CSIC), Campus UAB, 08193-Cerdanyola, Spain, and
Department of Chemistry, Loughborough UniVersity, Loughborough, Leicestershire LE11 3TU, U.K.
amat@ub.edu; joanbosch@ub.edu
ReceiVed March 19, 2007
An enantioselective two-step route to substituted benzo[a]- and indolo[2,3-a]quinolizidines has been
developed. It consists of (i) a stereoselective cyclocondensation of a racemic or prochiral δ-oxo(di)ester
with either (S)-(3,4-dimethoxyphenyl)alaninol or (S)-tryptophanol in a process involving a dynamic kinetic
resolution and/or the differentiation of enantiotopic or diastereotopic ester groups, and (ii) a subsequent
stereocontrolled cyclization on the aromatic ring taking advantage of the masked N-acyl iminium ion
present in the resulting oxazolopiperidone lactams.
Introduction
to lactams that already incorporate the carbon substitutents on
the heterocyclic ring (Scheme 1).3 In the above cycloconden-
sations, the chiral aminoalcohol constitutes a chiral latent form
of ammonia, and a later debenzylation is needed to remove the
phenylethanol appendage.
Aminoalcohol-derived oxazolopiperidone lactams have proven
to be exceptionally versatile building blocks for the enantiose-
lective construction of structurally diverse piperidine-containing
natural products and bioactive compounds.1 These lactams are
easily accessible by the cyclocondensation reaction of δ-oxoacid
derivatives with chiral nonracemic aminoalcohols, generally
phenylglycinol, and allow the substituents to be introduced at
the different ring positions in a regio- and stereocontrolled
manner, providing access to enantiopure polysubstituted pip-
eridines bearing virtually any type of substitution pattern and
also to quinolizidines, indolizidines, perhydroquinolines, hy-
droisoquinolines, as well as indole alkaloids.2 Particularly
interesting are cyclocondensation reactions of phenylglycinol
with racemic or prochiral δ-oxo(di)acid derivatives in processes
involving dynamic kinetic resolution and/or differentiation of
enantiotopic or diastereotopic ester groups, as they lead directly
Results and Discussion
We present here an enantioselective two-step route to
substituted benzo[a]- and indolo[2,3-a]quinolizidines, two het-
(2) (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.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org.
Chem. 2003, 68, 1919. (c) Amat, M.; Escolano, C.; Llor, N.; Huguet, M.;
Pe´rez, M.; Bosch, J. Tetrahedron: Asymmetry 2003, 14, 1679. (d)
Casamitjana, N.; Amat, M.; Llor, N.; Carreras, M.; Pujol, X.; Ferna´ndez,
M. M.; Lo´pez, V.; Molins, E.; Miravitlles, C.; Bosch, J. Tetrahedron:
Asymmetry 2003, 14, 2033. (e) Amat, M.; Lozano, O.; Escolano, C.; Molins,
E.; Bosch, J. J. Org. Chem. 2007, 72, 4431.
(3) (a) Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.; Pe´rez, M.; Bosch, J.
Angew. Chem., Int. Ed. 2002, 41, 335. (b) Amat, M.; Canto´, M.; Llor, N.;
Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67,
5343. (c) Amat, M.; Pe´rez, M.; Llor, N.; Escolano, C.; Luque, F. J.; Molins,
E.; Bosch, J. J. Org. Chem. 2004, 69, 8681. (d) Amat, M.; Escolano, C.;
Lozano, O.; Go´mez-Esque´, A.; Griera, R.; Molins, E.; Bosch, J. J. Org.
Chem. 2006, 71, 3804. (e) Amat, M.; Bassas, O.; Llor, N.; Canto´, M.; Pe´rez,
M.; Molins, E.; Bosch, J. Chem. Eur. J. 2006, 12, 7872. (f) Amat, M.;
Escolano, C.; Go´mez-Esque´, A.; Lozano, O.; Llor, N.; Griera, R.; Molins,
E.; Bosch, J. Tetrahedron: Asymmetry 2006, 17, 1581.
† University of Barcelona.
‡ Institut de Cie`ncia de Materials.
§ Loughborough University.
(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/jo070539g CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/05/2007
J. Org. Chem. 2007, 72, 5193-5201
5193

Amat et al.
SCHEME 1. Enantioselective Synthesis of Polysubstituted
Piperidines
SCHEME 2. Synthetic Strategy
FIGURE 1. Benzo[a]- and indolo[2,3-a]quinolizidine alkaloids.
chirally labile stereocenter capable of undergoing in situ
epimerization during the reaction, took place in good chemical
yield and excellent stereoselectivity (dr ∼ 5:1), leading to one
of the four possible enantiopure stereoisomeric lactams as the
major product (4b, isolated in 77% yield) in a process involving
a dynamic kinetic resolution (DKR)8 of the racemic substrate
(Scheme 3). Minor amounts of the diastereoisomer at the 8 and
8a positions (4b′) were also formed. Although such DKR
processes represent a useful tool for preparing enantiopure chiral
compounds, they have been rarely used in synthetic sequences
due to the structural restrictions imposed by the substrate.
A stereoselective cyclocondensation also occurred from
oxodiester 3c in a process involving the desymmetrization9,10
of two enantiotopic acetate chains. Enantiopure lactam 4c was
isolated in 67% yield along with minor amounts of the
diastereoisomer at the 7 and 8a positions (4c′).11 Even more
interestingly, treatment of racemic δ-oxodiester 3d with ami-
noalcohol 1 took place stereoselectively, with generation of three
stereogenic centers in a single synthetic step, to lead to one of
erocyclic systems present in numerous monoterpenoid-derived
alkaloids (Figure 1),4 many of which possess considerable
pharmacological and therapeutic interest.5
Our approach involves (i) the stereoselective cycloconden-
sation of a racemic or prochiral δ-oxo(di)ester with either (3,4-
dimethoxyphenyl)alaninol (1) or tryptophanol (2) and (ii) a
subsequent stereocontrolled cyclization on the aromatic ring
taking advantage of the masked N-acyl iminium ion present in
the resulting bicyclic lactams (Scheme 2).6 As δ-oxoester
partners we selected the racemic derivative 3b, prochiral
δ-oxodiesters 3c and 3e bearing two enantiotopic ester chains,
and racemic δ-oxodiester 3d bearing two diastereotopic ester
chains. The aminoalcohol used as the chiral inductor in the
cyclocondensation reaction not only constitutes the source of
chirality but is also used to assemble the final target polycyclic
products.7
(7) For a related approach using unbranched oxoester 3a, ultimately
leading to unsubstituted benzo[a]- and indolo[2,3-a]quinolizidines, see: (a)
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. (b) Allin, S.
M.; Thomas, C. I.; Allard, J. E.; Doyle, K.; Elsegood, M. R. J. Tetrahedron
Lett. 2004, 45, 7103. (c) For an asymmetric synthesis of both enantiomers
of the indole alkaloid deplancheine, see: Allin, S. M.; Thomas, C. I.; Doyle,
K.; Elsegood, M. R. J. J. Org. Chem. 2005, 70, 357.
(8) For reviews, see: (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull.
Chem. Soc. Jpn. 1995, 68, 36. (b). Ward, R. S. Tetrahedron: Asymmetry
1995, 6, 1475.4. (c) Caddick, S.; Jenkins, K. Chem. Soc. ReV. 1996, 25,
447. (d) Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem. Soc. ReV.
2001, 30, 321. (e) Pellissier, H. Tetrahedron 2003, 59, 8291.
(9) For reviews, see: (a) Ward, R. S. Chem. Soc. ReV. 1990, 19, 1. (b)
Danieli, B.; Lesma, G.; Passarella, D.; Riva, S. In AdVances in the Use of
Synthons in Organic Chemistry, Vol. 1; Dondoni, A., Eds.; JAI Press:
London, 1993, pp 143. (c) Schoffers, E.; Golebiowski, A.; Johnson, C. R.
Tetrahedron 1996, 52, 3769. (d) Willis, M. C. J. Chem. Soc. Perkin Trans.
1 1999, 1765. (e) Danieli, B.; Lesma, G.; Passarella, D.; Silvani, A. Curr.
Org. Chem. 2000, 4, 231. (f) Garc´ıa- Urdiales, E.; Alfonso, I.; Gotor, V.
Chem. ReV. 2005, 105, 313.
(10) For the use of tryptophanol in the desymmetrization of meso-
trihydroxylated glutaraldehyde, see: Tite, T.; Lallemand, M.-C.; Poupon,
E.; Kunesch, N.; Tillequin, F.; Gravier-Pelletier, C.; Le Merrer, Y.; Husson
H.-P. Biorg. Med. Chem. 2004, 12, 5091.
Cyclocondensation of the L-DOPA-derived aminoalcohol 1
with racemic γ-alkyl δ-oxoester 3b, which incorporates a
(4) Sto¨ckigt, J.; Ruppert, M. In ComprehensiVe Natural Products; Barton,
D., Nakanishi, K., Eds.; Elsevier: New York, 1999; Vol. 4, pp 109-138.
(5) (a) Neuss, N. In Indole and Biogenetically Related Alkaloids;
Philipson, J. D., Zenk, M. H., Eds.; Academic Press: London, 1980; Chapter
17. (b) Dewick, P. Medicinal Natural Products. A Biosynthetic Approach;
Wiley: Chichester, 2002.
(6) For preliminary accounts of part of this work, see: (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.; Duffy, L. J.; McKee, V.; Edgar,
M.; Amat, M.; Bassas, O.; Santos, M. M. M.; Bosch, J. Tetrahedron Lett.
2006, 47, 5713.
(11) The absolute configuration of lactams 4c, 4c′, and 8e, benzo[a]-
quinolizidines 5b-d, and indolo[2,3-a]quinolizidines 9b′, 1-epi-9b, 1-epi-
9b′, and 9d was unambiguously confirmed by X-ray crystallographic
analysis (see supporting information; for X-ray data of 5c, see reference
6b and CCDC code 297432).
5194 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of Benzo[a]- and Indolo[2,3-a]quinolizidines
SCHEME 3. Cyclocondensation Reactions from (S)-3,4-Dimethoxyphenylalaninol: Enantioselective Synthesis of Substituted
Benzo[a]quinolizidines
the eight possible stereoisomeric lactams (4d) in 60% yield.
Notably, this reaction involves a dynamic kinetic resolution of
the racemic substrate, with subsequent preferential cyclization
of one of the two diastereotopic acetate chains. Minor amounts
of the diastereoisomer at the 7, 8, and 8a positions (4d′) were
also isolated.
approach16 of the aromatic ring to the electrophilic carbon center
in the conformation A depicted in Figure 2. The alternative
cyclization via the chairlike conformation B would be disfavored
because of severe A(1,3) strain between the pseudoequatorial
hydroxymethyl substituent (complexed with the Lewis acid) and
the lactam carbonyl group in the transition state. It should be
noted that the hydroxymethyl substituent plays a decisive role
as a stereocontrol element in determining the relative stereo-
chemistry of the C-11b stereocenter generated in the cyclization
step.17 The A(1,3) strain between the CH2OH/CdO (and R1/d
CH when R1 is ethyl) groups in the transition state derived from
B is higher than the syn-axial 1,3-interactions of the substituents
R1 (ethyl) and/or R2 (acetate chain) in the transition state coming
from A. In accordance with this interpretation, (i) a 6,11b-trans
benzoquinolizidine was also obtained as a single stereoisomer
in the cyclization (TiCl4) of the deethyl analogue of 4b;7a (ii)
there is no stereocontrol in related kinetically controlled
cyclizations of six-membered N-acyliminium ions lacking the
hydroxymethyl substituent but bearing an ethyl substituent at
the carbon adjacent (R) to the electrophilic center18 (both type-A
and -B conformations are similarly favored); and (iii) a
stereoselectivity opposite to that observed in the cyclization of
4c was found in cyclizations from substrates bearing only a â
The high stereoselectivities observed in the above cyclocon-
densation reactions can be accounted for by considering that
(i) the initially formed mixtures of oxazolidines are in equilib-
rium via the corresponding imines/enamines and (ii) the final
irreversible lactamization occurs faster from a cis-oxazolidine
intermediate via a transition state in which all the substituents
in the incipient chairlike six-membered lactams are equatorial.3e
Intramolecular R-amidoalkylation of the above L-DOPA-
derived12 oxazolopiperidone lactams 4b-d took place stereo-
selectively by treatment with BF3·Et2O or TiCl4 to give the
respective enantiopure benzo[a]quinolizidines 5b-d11,13 as
single stereoisomers detectable by NMR. Taking into account
that N-acyliminium ion cyclizations14 upon the 3,4-dimethoxy-
benzene ring are known to occur under kinetic control and are
devoid of stereochemical equilibration,14c,15 the 6,11b-trans
relationship resulting from the above cyclizations can be
rationalized on the basis of a stereoelectronically controlled axial
(12) For diastereoselective intramolecular R-amidoalkylation reactions
of L-DOPA-derived five-membered N-acyliminium ions, see: Garc´ıa, E.;
Arrasate, S.; Lete, E.; Sotomayor, N. J. Org. Chem. 2005, 70, 10368 and
references therein.
(13) For a recent review on the asymmetric synthesis of isoquinoline
alkaloids, see: Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004,
104, 3341.
(14) For a review on the Pictet-Spengler condensation, including
mechanisms for cyclization and isomerization, see: (a) Cox, E. D.; Cook,
J. M. Chem. ReV. 1995, 95, 1797. For recent reviews on the chemistry and
cyclizations of N-acyliminium ions, see: (b) Speckamp, W. N.; Moolenaar,
M. J. Tetrahedron 2000, 56, 3817. (c) Maryanoff, B. E.; Zhang, H.-C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431.
(15) Maryanoff, B. E.; McComsey, D. F.; Duhl-Emswiler, B. A. J. Org.
Chem. 1983, 48, 5062.
(16) Deslongchamps, P. In Stereoelectronic Effects in Organic Chemistry;
Baldwin, J. E., Ed.; Pergamon: Oxford, 1983.
(17) 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.; Almond, H. R., Jr.; Mutter, M. S.; Bemis, G. W.; Whittle, R. R.;
Olofson, R. A. J. Org. Chem. 1986, 51, 1341. (b) Huizenga, R. H.; Pandit,
U. K. Tetrahedron 1992, 48, 6521. (c) Allin, S. M.; Northfield, C. J.; Page,
M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1998, 39, 4905. (d) Heaney, H.;
Taha, M. O. Tetrahedron Lett. 2000, 41, 1993. (e) Bahajaj, A. A.; Vernon,
J. M.; Wilson, G. D. J. Chem. Soc. Perkin Trans. 1 2001, 1446. (f) Nielsen,
T. E.; Meldal, M. J. Org. Chem. 2004, 69, 3765. See also refs 7 and 15.
(18) Kalaus, G.; Gyo¨ry, P.; Kajta´r-Peredy, M.; Radics, L.; Szabo´, L.;
Sza´ntay, C. Chem. Ber. 1981, 114, 1476.
J. Org. Chem, Vol. 72, No. 14, 2007 5195

Amat et al.
SCHEME 4. Cyclocondensation Reactions from
(S)-Tryptophanol
FIGURE 2. Stereochemical outcome of N-acyliminium cyclization
reaction.
stereogenic center19 (a type-B conformation operates, in which
the substituent R2 is equatorial).
The use of HCl (6 M in methanol, 50 °C, 24 h) in the above
cyclizations was less satisfactory from the synthetic standpoint.
Although these cyclizations took place in high overall yield
(∼80%) and complete stereoselectivity, mixtures of the expected
6,11b-trans benzoquinolizidines 5b-d and the corresponding
chlorides 6b-d were formed (1-2:1 ratio). Interestingly, when
the cyclization of 4b using HCl was carried out at room
temperature, a mixture of diastereoisomeric lactams 4b and 4b′
(approximate 1:3 ratio) and minor amounts of the cyclized
product 5b were formed. This result indicates that under these
conditions the equilibration20 of the 3,8a-cis lactam 4b to the
most stable all-trans isomer 4b′ is faster than cyclization upon
the benzene ring and that cyclization occurs exclusively from
the N-acyliminium ion derived from 4b (A; R1 ) Et, R2H in
Figure 2). The cyclization of the N-acyliminium ion derived
from 4b′ should overcome the A(1,3) strain between the equatorial
ethyl group and the hydrogen atom of the iminium cation. In
agreement with this interpretation, cyclization (6.5 M HCl in
methanol, 50 °C, 24 h) of pure lactam 4b′ (the minor
stereoisomer in the cyclocondensation of 3b) occurred with
inversion of the configuration of the stereocenter adjacent to
the iminium cation, leading to a mixture (71% overall yield) of
the same benzoquinolizidine alcohol (5b) and chloride (6b)
previously obtained from 4b.
with differentiation of diastereotopic acetate chains,21 respec-
tively. In these cases, minor amounts of the respective diaste-
reoisomers at the 8,8a and 7,8,8a positions (8e′ and 8d′,
respectively) were also isolated. As in the above L-DOPA-
derived lactams, the relative stereochemistry of the oxazolidine
moiety in the major lactams 8b, 8d, and 8e11 was cis.
Cyclization of 8b by intramolecular R-amidoalkylation on
the indole 2-position occurred smoothly, under kinetic control,
by treatment with HCl (1.2 M in EtOH, rt, 24 h) to give the
6,12b-trans indoloquinolizidine 9b in 80% yield (Scheme 5).
Minor amounts (13% yield) of the epimeric 6,12b-cis indolo-
quinolizidine 9b′ were also isolated.11 This result is consistent
with that reported for the cyclization of the deethyl analogue
of 8b: a single 6,12b-trans indoloquinolizidine was obtained
with 2 M HCl, whereas a 5:2 diastereoisomeric mixture of trans/
cis isomers was formed using TiCl4.7b In the indole series, the
removal of the hydroxymethyl substituent required the protection
of the indole nitrogen as a Boc derivative. In this way, following
the protocol reported by Allin,7b,c 9b was satisfactorily converted
to indoloquinolizidine 10 as shown in Scheme 5.
The removal of the hydroxymethyl appendage of 5c to give
the enantiopure cis-benzo[a]quinolizidine-2-acetate 7 was ac-
complished following the procedure recently developed by
Allin:7b,c by oxidation to a carboxylic acid followed by a radical
reductive decarbonylation of the corresponding seleno ester.
Highly stereoselective cyclocondensations also occurred from
tryptophanol (2). Thus, reaction with racemic oxoester 3b
afforded enantiopure lactam 8b in 76% yield, along with minor
amounts (11%) of the 8,8a-diastereoisomer 8b′, in a process
again involving a dynamic kinetic resolution with epimerization
of the stereogenic center R to the aldehyde carbonyl group
(Scheme 4). Prochiral diester 3e, in turn, reacted with tryp-
tophanol to give the enantiopure lactam 8e (70% yield), whereas
racemic diester 3d led to substituted lactam 8d (62% yield) in
cyclocondensations involving the desymmetrization of two
enantiotopic propionate chains and a dynamic kinetic resolution
Remarkably, the use of BF3·Et2O (CH2Cl2, reflux, 24 h) in
the cyclization of 8b resulted in a dramatic change in the
stereoselectivity as the 6,12b-cis indoloquinolizidine 9b′ was
obtained as the major product (61% yield). Minor amounts
(19) (a) Takano, S.; Takahashi, M.; Ogasawara, K. J. Am. Chem. Soc.
1980, 102, 4282. (b) Pancrazi, A.; Kervagoret, J.; Khuong-Huu, Q.
Tetrahedron Lett. 1991, 32, 4483. (c) Danieli, B.; Lesma, G.; Mauro, M.;
Palmisano, G.; Passarella, D. Tetrahedron 1994, 50, 8837.
(20) For similar epimerizations of phenylglycinol-derived cis-oxazol-
opiperidone lactams to the trans-isomers, see: Amat, M.; Escolano, C.;
Go´mez-Esque´, A.; Lozano, O.; Llor, N.; Griera, R.; Molins, E.; Bosch, J.
Tetrahedron: Asymmetry 2006, 17, 1581. See also ref 2a.
(21) For early precedents of the discrimination of diastereotopic acetal-
dehyde chains in the context of the synthesis of indole alkaloids, see: (a)
Masamune, S.; Ang, S. K.; Egli, C.; Nakatsuka, N.; Sarkar, S. K.; Yasunari,
Y. J. Am. Chem. Soc. 1967, 89, 2506. (b) van Tamelen, E. E.; Oliver, L.
K. J. Am. Chem. Soc. 1970, 92, 2136.
5196 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of Benzo[a]- and Indolo[2,3-a]quinolizidines
SCHEME 5. Stereocontrolled Synthesis of
1-Ethylindolo[2,3-a]quinolizidines
In contrast to the above cyclizations from 8b, cyclization of
the minor lactam 8b′ took place with the same stereoselectivity
whether using BF3·Et2O (CH2Cl2, reflux, 24 h) or HCl (2 M in
ethanol, rt, 3 days) to give a single 6,12b-trans indoloquino-
lizidine 1-epi-9b11 (67 and 86% yields, respectively) (Scheme
6). A similar stereoselectivity was observed in the acid-promoted
cyclization of lactam 8d: the 6,12b-trans indoloquinolizidine
9d11 was the only isolable product, although in moderate yield
(35%), when using BF3·Et2O (CH2Cl2, reflux, 14 h) and the
major isomer (48%) with HCl (6.5 M in MeOH, rt, 25 h). Under
the latter conditions, a minor (29%) C-1 isomeric indoloquino-
lizidine 9d′ was also isolated.
Conclusion
Oxazolopiperidone lactams derived from (3,4-dimethoxyphe-
nyl)alaninol or tryptophanol significantly expand the potential
and scope of chiral bicyclic lactams for the enantioselective
synthesis of piperidine-containing derivatives, providing a two-
step route to substituted enantiopure benzo[a]- and indolo[2,3-
a]quinolizidines. (3,4-Dimethoxyphenyl)alaninol and tryptoph-
anol not only constitute the source of chirality, acting as chiral
inductors in highly stereoselective cyclocondensation reactions
involving dynamic kinetic resolution and/or differentiation of
enantiotopic or diastereotopic ester chains, but are also used to
assemble the final polycyclic targets via an intramolecular
R-amidoalkylation reaction in which the temporary hydroxy-
methyl appendage acts as an efficient element of stereocontrol.
SCHEME 6. Enantioselective Synthesis of Substituted
Indolo[2,3-a]quinolizidines
Experimental Section
General Procedure for Cyclocondensation Reactions. (S)-3-
(3,4-Dimethoxyphenyl)alaninol 1 or (S)-tryptophanol 2 (1.1 equiv)
was added to a stirred solution of δ-oxo(di)ester 3b-e (1 equiv)
in anhydrous toluene. The mixture was heated at reflux under
Dean-Stark conditions. Then, the solvent was removed under
reduced pressure to yield a residue, which was chromatographed.
[(3S,8R,8aS) and (3S,8S,8aR)]-3-(3,4-Dimethoxybenzyl)-8-
ethyl-5-oxo-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (4b)
and (4b′). Following the general procedure, aminoalcohol (1; 1.47
g, 6.96 mmol) and methyl 4-formylhexanoate (3b; 1 g, 6.32 mmol)
in toluene (25 mL) for 18 h afforded a mixture of lactams 4b (1.55
g, 77%) and 4b′ (0.30 g, 15%), which were separated by flash
chromatography (1:1 hexane-EtOAc to EtOAc). 4b: IR (film)
1649 cm-1; 1H NMR (400 MHz) δ 0.98 (t, J ) 7.8 Hz, 3H, CH3),
1.20-1.47 (m, 3H, H-7, CH2CH3, H-8), 1.65-1.80 (m, 1H, CH2-
CH3), 1.96-2.08 (m, 1H, H-7), 2.38-2.47 (m, 3H, CH2Ar, H-6),
3.55 (dd, J ) 13.2, 2.4 Hz, 1H, CH2Ar), 3.67 (ddd, J ) 9.0, 8.0,
1.2 Hz, 1H, H-2), 3.86 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 4.01
(dd, J ) 9.0, 0.6 Hz, 1H, H-2), 4.13-4.20 (m, 1H, H-3), 4.34 (d,
J ) 9.0 Hz, 1H, H-8a), 6.75.4-6.82 (m, 3H, ArH); 13C NMR (100.6
MHz) δ 10.8 (CH3), 23.4 (C-7), 23.9 (CH2CH3), 31.3 (C-6), 36.4
(CH2Ar), 40.9 (C-8), 55.7 and 55.8 (CH3O), 57.0 (C-3), 69.0 (C-
2), 92.5 (C-8a), 111.1 (CH), 112.5 (CH), 121.4 (CH), 130.6, 147.5
and 148.8 (C), 167.6 (NCO); MS-EI m/z 319 (M+, 15), 178 (15),
168 (100), 151 (20), 126 (26); HMRS C18H25NO4, 319.1784; found,
319.1783. 4b′: IR (film) 1650 cm-1; 1H NMR (400 MHz) δ 0.96
(t, J ) 7.6 Hz, 3H, CH3), 1.23-1.42 (m, 3H, H-7, CH2CH3, H-8),
1.65-1.74 (m, 1H, CH2CH3), 1.88-1.92 (m, 1H, H-7), 2.30-2.39
(m, 1H, H-6), 2.55 (dd, J ) 18.2, 5.0 Hz, 1H, H-6), 2.73 (dd, J )
18.2, 9.6 Hz, 1H, CH2Ar), 3.20 (dd, J ) 13.6, 3.6 Hz, 1H, CH2-
Ar), 3.62 (dd, J ) 9.2, 7.6 Hz, 1H, H-2), 3.86 (s, 6H, CH3O), 4.01
(dd, J ) 8.8, 7.6 Hz, 1H, H-2), 4.20 (d, J ) 7.6 Hz, 1H, H-8a),
4.45 (ddd, J ) 16.4, 7.6, 3.6 Hz, 1H, H-3), 6.71-6.80 (m, 3H,
ArH); 13C NMR (100.6 MHz) δ 10.9 (CH3), 22.8 (C-7), 24.4 (CH2-
CH3), 31.5 (C-6), 37.1 (CH2Ar), 40.9 (C-8), 55.3 (C-3), 55.7 and
(13%) of the trans epimer 9b and, in some experiments
conducted on a larger scale, trace amounts of a third indolo-
quinolizidine 1-epi-9b′ were also isolated.11 Interestingly, two
C-12b epimeric indoloquinolizidines can be accessed from a
single tryptophanol-derived lactam 8b by an appropriate choice
of acid for the cyclization. Even more satisfactorily in terms of
chemical yield, lactam 8b was converted to pentacyclic oxazo-
lidine 11 in 73% overall yield by sequential treatment with BF3·
Et2O and NaBH4 in methanol. Under these conditions, indolo-
quinolizidine 9b was isolated (13% yield) as a byproduct,
showing that only the major isomer 9b′ in the initially formed
9b + 9b′ mixture undergoes partial reduction of the lactam
carbonyl group to give an iminium species, which is intramo-
lecularly trapped by the hydroxy group. A subsequent reductive
cleavage with alane of the oxazolidone ring present in 11
gave the enantiopure 6,12b-cis indoloquinolizidine 12 in 70%
yield.
J. Org. Chem, Vol. 72, No. 14, 2007 5197

Amat et al.
55.8 (CH3O), 69.1 (C-2), 91.3 (C-8a), 111.1 (CH), 112.5 (CH),
121.4 (CH), 129.3, 147.7 and 148.9 (C), 168.6 (NCO); [R]D22
+33.5 (c 1.0, CHCl3); MS-EI m/z 319 (M+, 12), 178 (13), 168
(100), 151 (23), 126 (25); HMRS C18H25NO4, 319.1784; found,
319.1783.
13.6, 3.6 Hz, 1H, CH2Ar), 3.63 (dd, J ) 8.4, 7.6 Hz, 1H, H-2),
3.70 (s, 3H, COOCH3), 3.86 (s, 3H, CH3O), 3.87 (s, 3H, CH3O),
4.01 (dd, J ) 8.4, 8.0 Hz, 1H, H-2), 4.37 (d, J ) 8.4 Hz, 1H,
H-8a), 4.42-4.49 (m, 1H, H-3), 6.67-6.85 (m, 3H, ArH); 13C NMR
(100.6 MHz) δ 9.6 (CH3), 20.7 (CH2CH3), 29.9 (C-7), 36.8 and
37.6 (C-6, CH2CO), 37.3 (CH2Ar), 43.4 (C-8), 51.8 (COOCH3),
55.3 (C-3), 55.8 and 55.9 (CH3O), 69.3 (C-2), 89.5 (C-8a), 111.2
(CH), 112.5 (CH), 121.4 (CH), 129.2 (C), 147.8 and 149.0 (C),
167.4 (C-5), 172.2 (COO); [R]2D2 +11.8 (c 0.52, CHCl3); MS-EI
m/z 391 (M+, 5), 240 (46), 208 (7), 178 (45), 166 (100), 151 (41);
HMRS C21H29NO6, 391.1995; found, 391.1995.
[(3S,7R,8aS) and (3S,7S,8aR)]-3-(3,4-Dimethoxybenzyl)-7-
(methoxycarbonylmethyl)-5-oxo-2,3,6,7,8,8a-hexahydro-5H-ox-
azolo[3,2-a]pyridine (4c) and (4c′). Following the general proce-
dure, (S)-3-(3,4-dimethoxyphenyl)alaninol (1; 1.94 g, 9.2 mmol)
and dimethyl 3-(2-oxoethyl)glutarate (3c; 1.86 g, 9.2 mmol) in
toluene (4 mL) for 24 h afforded a mixture of lactams 4c (2.23 g,
67%) and 4c′ (0.43 g, 13%), which were separated by flash
chromatography (19:1 Et2O-EtOH). 4c: IR (film) 1644, 1734
[(3S,8R,8aS) and (3S,8S,8aR)]-8-Ethyl-3-(3-indolylmethyl)-5-
oxo-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (8b) and
(8b′). Following the general procedure, (S)-tryptophanol (2; 530
mg, 2.78 mmol) and methyl 4-formylhexanoate (3b; 440 mg, 2.78
mmol) in toluene (6 mL) for 23 h afforded a mixture of lactams
8b (629 mg, 76%) and 8b′ (99 mg, 11%), which were separated
by flash chromatography (1:4 hexane-EtOAc to 1:9 hexane-
EtOAc). 8b: IR (film) 1628 cm-1; 1H NMR (300 MHz) δ 1.00 (t,
J ) 7.2 Hz, 3H, CH3), 1.28 (m, 1H, CH2CH3), 1.38 (m, 1H, H-8),
1.79 (m, 1H, CH2CH3), 2.02 (m, 1H, H-7), 2.47 (m, 2H, H-6), 2.62
(dd, J ) 14.1, 10.5 Hz, 1H, CH2 ind), 3.66 (ddd, J ) 7.5, 6.0, 1.5
Hz, 1H, H-2), 3.76 (dt, J ) 14.1, 1.5 Hz, 1H, CH2 ind), 4.02 (d, J
) 11.7 Hz, 1H, H-2), 4.30 (ddd, J ) 9.6, 6.0, 3.0 Hz, 1H, H-3),
4.36 (d, J ) 8.7 Hz, 1H, H-8a), 7.05 (s, 1H, ArH), 7.14 (ddd, J )
7.2, 7.2, 1.2 Hz, 1H, ArH), 7.20 (ddd, J ) 7.2, 7.2, 1.2 Hz, ArH),
7.35 (d, J ) 7.2 Hz, 1H, ArH), 7.85 (d, J ) 7.2 Hz, 1H, ArH),
8.11 (br s, 1H, NH); 13C NMR (75.4 MHz) δ 10.9 (CH3), 23.5
(C-7), 24.0 (CH2CH3), 26.9 (CH2 ind), 31.4 (C-6), 41.0 (C-8), 56.3
(C-3), 69.8 (C-2), 92.6 (C-8a), 111.0 (CH), 112.3 (C), 119.2 (CH),
119.3 (CH), 121.9 (CH), 122.3 (CH), 127.5 and 136.1 (C), 167.9
1
cm-1; H NMR (400 MHz) δ 1.27 (m, 1H, H-8), 2.09 (dd, J )
17.6, 10.4 Hz, 1H, H-6), 2.34-2.41 (m, 3H, H-7, CH2CO), 2.47
(dd, J ) 13.2, 10.0 Hz, 1H, CH2Ar), 2.60 (dd, J ) 17.6, 4.8 Hz,
1H, H-6), 3.54 (dd, J ) 13.2, 2.6 Hz, 1H, CH2Ar), 3.70 (s, 3H,
COOCH3), 3.73 (ddd, J ) 9.6, 6.4, 1.2 Hz, 1H, H-2), 3.86 (s, 3H,
CH3O), 3.87 (s, 3H, CH3O), 4.03 (d, J ) 9.2 Hz, 1H, H-2), 4.14-
4.19 (m, 1H, H-3), 4.72 (dd, J ) 16.4, 3.2 Hz, 1H, H-8a), 6.74-
6.81 (m, 3H, ArH); 13C NMR (100.6 MHz) δ 21.7 (C-7), 34.4 (C-
8), 36.4 (CH2Ar), 37.6 (C.6), 40.0 (CH2CO), 51.7 (COOCH3), 55.8
and 55.9 (CH3O), 56.7 (C-3), 69.4 (C-2), 88.3 (C-8a), 111.1 (CH),
112.5 (CH), 121.5 (CH), 130.5 (C), 147.7 and 148.9 (C), 166.5
(NCO), 171.7 (COO); mp 108-109 °C (Et2O); [R]22 +4.7 (c 0.81,
CHCl3). Anal. Calcd for C19H25NO6: C, 62.80; HD, 6.93; N, 3.85.
Found: C, 62.70; H, 6.85; N, 3.88. 4c′: IR (film) 1644, 1735 cm-1
;
1H NMR (400 MHz) δ 1.25 (td, J ) 12.4, 10.0 Hz, 1H, H-8), 2.03
(dd, J ) 18.0, 11.2 Hz, 1H, H-6), 2.24-2.38 (m, 4H, H-7, H-8
and CH2CO), 2.67 (dd, J ) 18.0, 4.8, 1.6 Hz, 1H, H-6), 2.74 (dd,
J ) 13.6, 9.0 Hz, 1H, CH2Ar), 3.19 (dd, J ) 13.6, 3.6 Hz, 1H,
CH2Ar), 3.65 (dd, J ) 8.8, 7.6 Hz, 1H, H-2), 3.70 (s, 3H, CH3-
OCO), 3.86 (s, 3H, CH3O), 3.87 (s, 3H, CH3O), 4.04 (d, J ) 8.8,
7.6 Hz, 1H, H-2), 4.45 (m, 1H, H-3), 4.57 (dd, J ) 9.2, 4.4 Hz,
1H, H-8a), 6.70-6.80 (m, 3H, ArH); 13C NMR (100.6 MHz) δ
26.6 (C-7), 34.1 (C-8), 37.2 (CH2Ar), 37.6 (C-6), 39.6 (CH2CO),
51.8 (CH3O2C), 55.0 (C-3), 55.8 (CH3O), 69.5 (C-2), 86.7 (C-8a),
111.1 (CH), 112.5 (CH), 121.4 (CH), 129.1, 147.8 and 148.9 (C),
167.4 (NCO), 171.7 (COO); mp 88-90 °C (Et2O-EtOAc);
[R]2D2 +41.9 (c 0.41, CHCl3). Anal. Calcd for C19H25NO6: C,
62.80; H, 6.93; N, 3.85. Found: C, 62.55; H, 6.85; N, 3.76.
(C-5); mp 170-172 °C (Et2O-hexane); [R]22 -82.3 (c 1.2,
D
CHCl3). Anal. Calcd for C18H22N2O2‚1/4H2O: C, 71.38; H, 7.49;
N, 9.25. Found: C, 71.51; H, 7.69; N, 8.88. 8b′: IR (film) 1632
cm-1; 1H NMR (300 MHz) δ 0.91 (t, J ) 7.2 Hz, 3H, CH3), 1.27
(m, 3H, H-7, H-8 and CH2CH3), 1.64 (m, 1H, CH2CH3), 1.83 (m,
1H, H-7), 2.34 (ddd, J ) 18.0, 12.0, 6.6 Hz, 1H, H-6), 2.56 (dd, J
) 18.0, 5.1 Hz, 1H, H-6), 3.00 (dd, J ) 14.4, 9.0 Hz, 1H, CH2
ind), 3.33 (dd, J ) 14.4, 3.0 Hz, 1H, CH2 ind), 3.65 (dd, J ) 9.0,
7.5 Hz, 1H, H-2), 4.02 (dd, J ) 7.5, 1.2 Hz, 1H, H-2), 4.13 (d, J
) 8.1 Hz, 1H, H-8a), 4.60 (m, 1H, H-3), 6.96 (d, J ) 2.1 Hz, 1H,
H-2 ind), 7.09 (ddd, J ) 7.5, 7.5, 1.2 Hz, 1H, H-5 ind), 7.16 (ddd,
J ) 7.5, 7.5, 1.2 Hz, 1H, H-6 ind), 7.33 (d, J ) 7.5 Hz, 1H, H-7
ind), 7.69 (d, J ) 7,5 Hz, 1H, H-4 ind), 8.74 (b s, 1H, NH); 13C
NMR (75.4 MHz) δ 10.9 (CH3), 22.6 (C-7), 24.4 (CH2CH3), 27.4
(CH2 ind), 31.5 (C-6), 40.8 (C-8), 54.6 (C-3), 69.6 (C-2), 91.1 (C-
8a), 110.7 (C-3 ind), 111.1 (C-7 ind), 118.9 (C-4 ind), 119.2 (C-5
ind), 121.8 (C-6 ind), 122.6 (C-2 ind), 127.5 (C3a ind), 136.1 (C7a
[(3S,7R,8R,8aS) and (3S,7S,8S,8aR)]-3-(3,4-Dimethoxyben-
zyl)-8-ethyl-7-(methoxycarbonylmethyl)-5-oxo-2,3,6,7,8,8a-hexahy-
dro-5H-oxazolo[3,2-a]pyridine (4d) and (4d′). Following the
general procedure, (S)-3-(3,4-dimethoxyphenyl)alaninol (1; 353 mg,
1.67 mmol) and dimethyl 3-(1-formylpropyl)glutarate (3d; 350 mg,
1.52 mmol) in toluene (5 mL) for 24 h afforded a mixture of lactams
4d (353 mg, 59%) and 4d′ (100.6 mg, 17%), which were separated
by flash chromatography (1:1 hexane-EtOAc to EtOAc). 4d: IR
ind), 168.7 (NCO); mp 120-122 °C (Et2O-hexane); [R]22 +17.0
D
(c 0.2, CHCl3). Anal. Calcd for C18H22N2O2‚3/4H2O: C, 69.32; H,
1
(film) 1651, 1735 cm-1; H NMR (400 MHz) δ 0.97 (t, J ) 7.2
7.59; N, 8.98. Found: C, 69.14; H, 7.47; N, 8.76.
Hz, 3H, CH3), 1.41-1.47 (m, 1H, H-8), 1.56-1.71 (m, 2H, CH2-
CH3), 2.21-2.28 (m, 3H, H-6, H-7, CH2CO), 2.44 (dd, J ) 13.2,
10.8 Hz, 1H, CH2Ar), 2.50-2.59 (m, 2H, H-6, CH2CO), 3.49 (dd,
J ) 13.2, 2.4 Hz, 1H, CH2Ar), 3.70 (s, 3H, COOCH3), 3.70-3.74
(m, 1H, H-2), 3.86 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 4.01 (d, J
) 9.2 Hz, 1H, H-2), 4.15-4.20 (m, 1H, H-3), 4.53 (d, J ) 8.8 Hz,
1H, H-8a), 6.76-6.85 (m, 3H, ArH); 13C NMR (100.6 MHz) δ
9.9 (CH3), 22.0 (CH2CH3), 31.1 (C-7), 36.9 (CH2Ar), 37.4 and 38.4
(C-6 and CH2CO), 44.8 (C-8), 51.8 (COOCH3), 55.8 and 55.9
(CH3O), 56.8 (C-3), 69.5 (C-2), 90.8 (C-8a), 111.2 (CH), 112.5
(CH), 121.5 (CH), 130.5, 147.7 and 149.0 (C), 166.7 (NCO), 172.2
(COO); [R]2D2 -13.2 (c 0.54, CHCl3); MS-EI m/z 391 (M+, 11),
360 (2), 240 (49), 178 (22), 166 (100), 151 (30); HMRS C21H29-
[(3S,8S,8aS) and (3S,8R,8aR)]-3-(3-Indolylmethyl)-8-[2-(meth-
oxycarbonyl)ethyl]-5-oxo-2,3,6,7,8,8a-hexahydro-5H-oxazolo-
[3,2-a]pyridine (8e) and (8e′). Following the general procedure,
(S)-tryptophanol (2; 111 mg, 0.59 mmol) and dimethyl 4-formylpime-
late (3e; 125 mg, 0.58 mmol) in toluene (5 mL) for 24 h afforded
a mixture of lactams 8e (145 mg, 70%) and 8e′ (10 mg, 5%), which
were separated by flash chromatography (1:9 hexane-EtOAc to
9:1 EtOAc-EtOH). 8e: IR (film) 1627, 1734 cm-1; 1H NMR (300
MHz) δ 1.43 (m, 1H, H-1′), 1.62 (m, 2H, H-7 and H-8), 1.94 (m,
2H, H-7 and H-1′), 2.45 (m, 4H, H-6 and H-2′), 2.62 (dd, J )
13.8, 10.2 Hz, 1H, CH2 ind), 3.65 (m, 2H, H-2 and CH2 ind), 3.68
(s, 3H, CH3O), 4.00 (dd, J ) 9.0, 3.6 Hz, 1H, H-2), 4.27 (m, 1H,
H-3), 4.37 (d, J ) 8.1 Hz, 1H, H-8a), 7.01 (s, 1H, H-2 ind), 7.12
(td, J ) 7.5, 1.2 Hz, 1H, H-5 ind), 7.18 (td, J ) 7.5, 1.2 Hz, 1H,
H-6 ind), 7.34 (d, J ) 7.5 Hz, 1H, H-7 ind), 7.81 (d, J ) 7.5 Hz,
1H, H-4 ind), 8.41 (br s, 1H, NH); 13C NMR (75.4 MHz) δ 24.2
(C-1′), 26.8 (C-7), 26.8 (CH2 ind), 31.1 and 31.3 (C-6 and C-2′),
NO6, 391.1995; found, 391.1998. 4d′: IR (film) 1652, 1735 cm-1
;
1H NMR (400 MHz) δ 0.93 (t, J ) 7.6 Hz, 3H, CH3), 1.40-1.46
(m, 1H, H-8), 1.49-1.56 (m, 1H, CH2CH3), 1.64-1.74 (m, 1H,
CH2CH3), 2.10-2.18 (m, 2H, H-7, H-6), 2.30-2.61 (m, 3H, CH2-
CO, H-6), 2.71 (dd, J ) 13.6, 9.2 Hz, 1H, CH2Ar), 3.20 (dd, J )
5198 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of Benzo[a]- and Indolo[2,3-a]quinolizidines
38.8 (C-8), 51.6 (CH3O), 56.1 (C-3), 69.8 (C-2), 92.6 (C-8a), 111.0
(C-7 ind), 111.9 (C-3 ind), 119.0 (C-4 ind), 119.2 (C-5 ind), 121.8
(C-6 ind), 122.4 (C-2 ind), 127.4 (C-3a ind), 136.1 (C-7a ind), 167.7
the combined organic extracts were dried and concentrated. The
resulting residue was chromatographed (Et2O-MeOH) to afford
1
5b (69.5 mg, 70%): IR (film) 3100-3600, 1596 cm-1; H NMR
(NCO), 173.6 (COO); mp 132-134 °C (Et2O-hexane); [R]22
(400 MHz) δ 1.05 (t, J ) 7.2 Hz, 3H, CH3), 1.50-1.61 (m, 1H,
CH2CH3), 1.61-1.70 (m, 1H, CH2CH3), 1.72-1.80 (m, 1H, H-2),
2.01-2.09 (m, 1H, H-2), 2.20-2.27 (m, 1H, H-1), 2.33 (ddd, J )
17.6, 5.6, 4.4 Hz, 1H, H-3), 2.52 (ddd, J ) 17.6, 10.8, 6.4 Hz, 1H,
H-3), 2.61 (dd, J ) 15.2, 9.6 Hz, 1H, H-7), 2.96 (dd, J ) 15.2, 6.8
Hz, 1H, H-7), 3.61 (br s, 1H, OH), 3.66 (dd, J ) 11.2, 7.6 Hz,
CH2OH), 3.73 (dd, J ) 11.2, 3.6 Hz, CH2OH), 4.16 (dd, J ) 4.8
Hz, 1H, H-11b), 4.53-4.60 (m, 1H, H-6), 6.71 (s, 1H, ArH), 6.75.4
(s, 1H, ArH); 13C NMR (100.6 MHz) δ 11.6 (CH3), 21.4 (C-2),
25.0 (CH2CH3), 29.2 (C-3), 29.9 (C-7), 35.6 (C-1), 53.2 (C-6), 56.0
and 56.3 (CH3O), 57.1 (C-11b), 66.1 (CH2OH), 107.8 and 111.6
(C-8 and C-11), 128.0 and 129.4 (C-7a and C-11a), 147.4 and 148.4
(C-9 and C-10), 172.5 (C-4); mp 125-127 °C (Et2O-EtOAc);
[R]2D2 -36.7 (c 0.54, CHCl3). Anal. Calcd for C18H25NO4: C,
67.69; H, 7.89; N, 4.39. Found: C, 67.45; H, 7.80; N, 4.36.
D
-50.0 (c 1.0, CHCl3). Anal. Calcd for C20H24N2O4: C, 67.40; H,
6.79; N, 7.86. Found: C, 67.33; H, 6.89; N, 7.92. 8e′: IR (film)
1627, 1734 cm-1; 1H NMR (300 MHz) δ 1.33 (m, 1H, H-1′), 1.47
(m, 1H, H-8), 1.60 (m, 1H, H-7), 1.85 (m, 2H, H-7 and H-1′), 2.29-
2.67 (m, 4H, H-6 and H-2′), 3.02 (dd, J ) 14.0, 8.4 Hz, 1H, CH2
ind), 3.30 (dd, J ) 14.0, 3.3 Hz, 1H, CH2 ind), 3.65 (s, 3H, CH3O),
3.66 (m, 1H, H-2), 4.03 (dd, J ) 9.0, 7.8 Hz, 1H, H-2), 4.11 (d, J
) 8.1 Hz, 1H, H-8a), 4.58 (m, 1H, H-3), 6.99 (d, J ) 2.1 Hz, 1H,
H-2 ind), 7.10 (td, J ) 7.5, 1.2 Hz, 1H, H-5 ind), 7.15 (td, J ) 7.5,
1.2 Hz, 1H, H-6 ind), 7.34 (d, J ) 7.5 Hz, 1H, H-7 ind), 7.68 (d,
J ) 7.5 Hz, 1H, H-4 ind), 8.38 (br s, 1H, NH); 13C NMR (75.4
MHz) δ 23.7 (C-1′), 27.0 (C-7), 27.4 (CH2 ind), 31.4 (C-6 and
C-2′), 38.9 (C-8), 51.6 (CH3O), 54.5 (C-3), 69.6 (C-2), 91.4 (C-
8a), 110.9 (C-3 ind), 111.0 (C-7 ind), 119.0 (C-4 ind), 119.4 (C-5
ind), 122.0 (C-6 ind), 122.5 (C-2 ind), 127.6 (C-3a ind), 136.1 (C-
7a ind), 168.3 (C-5), 173.6 (NCO).
(2R,6S,11bR)-6-(Hydroxymethyl)-9,10-dimethoxy-2-(methox-
ycarbonylmethyl)-4-oxo-1,2,3,6,7,11b-hexahydrobenzo[a]quino-
lizine (5c). TiCl4 (3.3 mL, 30.3 mmol) was added dropwise to a
cooled (-78 °C) solution of lactam 4c (1.83 g, 5.04 mmol) in CH2-
Cl2 (100 mL), and the mixture was warmed at rt and stirred for 3.5
days. Saturated aqueous NH4Cl solution was added, and the mixture
was extracted with CH2Cl2. The dried combined organic extracts
were concentrated, and the resulting residue was chromatographed
(24:1 EtOAc-MeOH) to afford 5c (0.64 g, 35%): IR (film) 1615,
[(3S,7R,8R,8aS) and (3S,7S,8S,8aR)]-8-Ethyl-3-(3-indolyl-
methyl)-7-(methoxycarbonylmethyl)-5-oxo-2,3,6,7,8,8a-hexahy-
dro-5H-oxazolo[3,2-a]pyridine (8d) and (8d′). Following the
general procedure, (S)-tryptophanol (2; 350 mg, 1.84 mmol) and
dimethyl 3-(1-formylpropyl)glutarate (3d; 385 mg, 1.67 mmol) in
toluene (5 mL) for 9 h afforded lactams 8d (383 mg, 62%) and
8d′ (80 mg, 13%), which were separated by flash chromatography
1
1732, 3000-3500 cm-1; H NMR (400 MHz) δ 1.45 (ddd, J )
(1:5 hexane-EtOAc to EtOAc). 8d: IR (film) 1634, 1732 cm-1
;
1H NMR (400 MHz) δ 0.97 (t, J ) 7.6 Hz, 3H, CH3), 1.48 (m,
1H, H-8), 1.56-1.72 (m, 2H, CH2CH3), 2.24-2.31 (m, 3H, H-7,
H-6 and CH2CO), 2.52-2.60 (m, 2H, H-6 and CH2CO), 2.67 (dd,
J ) 13.6, 10.4 Hz, 1H, CH2 ind), 3.66 (m, 2H, H-2 and CH2 ind),
3.70 (s, 3H, CH3O), 4.03 (d, J ) 9.2 Hz, 1H, H-2), 4.30 (m, 1H,
H-3), 4.52 (d, J ) 8.4 Hz, 1H, H-8a), 7.03 (d, J ) 2.0 Hz, 1H, H-2
ind), 7.13 (td, J ) 7.6, 0.8 Hz, 1H, H-5 ind), 7.19 (td, J ) 7.6, 0.8
Hz, 1H, H-6 ind), 7.35 (d, J ) 7.6 Hz, 1H, H-7 ind), 7.81 (d, J )
7.6 Hz, 1H, H-4 ind), 8.25 (b s, 1H, NH); 13C NMR (100.6 MHz)
δ 9.9 (CH3), 22.0 (CH2CH3), 27.2 (CH2 ind), 31.2 (C-7), 37.3 and
38.5 (C-6 and CH2CO), 44.8 (C-8), 51.7 (CH3O), 55.9 (C-3), 70.2
(C-2), 90.8 (C-8a), 111.0 (C-7 ind), 112.4 (C-3 ind), 119.3 (C-4
ind), 119.5 (C-5 ind), 122.1 (C-6 ind), 122.3 (C-2 ind), 127.6 (C-
3a ind), 136.2 (C-7a ind), 166.8 (NCO), 172.2 (COO); [R]D22
-43.7 (c 0.65, CHCl3); HMRS C21H26N2O4, 370.1893; found,
370.1892. 8d′: IR (film) 1634, 1737 cm-1; 1H NMR (400 MHz) δ
0.86 (t, J ) 7.6 Hz, 3H, CH3), 1.40 (m, 1H, H-8), 1.48 (m, 1H,
CH2CH3), 1.63 (m, 1H, CH2CH3), 2.13 (m, 3H, H-7, H-6 and CH2-
CO), 2.55 and 2.70 (2m, 1H, H-6 or CH2CO), 3.01 (dd, J ) 14.4,
8.8 Hz, 1H, CH2 ind), 3.33 (ddd, J ) 14.4, 3.2, 0.4 Hz, 1H, CH2
ind), 3.37 (dd, J ) 9.2, 7.2 Hz, 1H, H-2), 3.70 (s, 3H, CH3O), 4.03
(dd, J ) 9.2, 7.6 Hz, 1H, H-2), 4.31 (d, J ) 8.0 Hz, 1H, H-8a),
4.62 (m, 1H, H-3), 7.02 (d, J ) 2.0 Hz, 1H, H-2 ind), 7.13 (td, J
) 7.2, 1.2 Hz, 1H, H-5 ind), 7.18 (td, J ) 7.2, 1.2 Hz, 1H, H-6
ind), 7.36 (d, J ) 7.2 Hz, 1H, H-4 ind), 7.70 (d, J ) 7.2 Hz, 1H,
H-7 ind), 8.21 (br s, 1H, NH); 13C NMR (100.6 MHz) δ 9.5 (CH3),
20.6 (CH2CH3), 27.5 (CH2 ind), 29.8 (C-7), 36.8 and 37.6 (C-6
and CH2CO), 43.3 (C-8), 51.8 (CH3O), 54.6 (C-3), 69.7 (C-2), 89.3
(C-8a), 111.1 (C-3 ind), 111.2 (C-7 ind), 119.1 (C-4 ind), 119.6
(C-5 ind), 122.2 (C-6 ind), 122.5 (C-2 ind), 127.7 (C-3a ind), 136.2
(C-7a ind), 167.5 (NCO), 172.2 (COO); [R]2D2 -31.0 (c 2.27,
CHCl3); HMRS C21H26N2O4, 370.1893; found, 370.1892.
12.8, 12.4, 12.0 Hz, 1H, H-1), 2.16 (dd, J ) 17.2, 11.2 Hz, 1H,
H-3), 2.37-2.39 (m, 2H, CH2CO), 2.55-2.58 (m, 2H, H-1 and
H-2), 2.63 (d, J ) 16.4 Hz, 1H, H-7), 2.73 (d, J ) 17.2 Hz, 1H,
H-3), 3.01 (dd, J ) 16.4, 5.2 Hz, 1H, H-7), 3.53-3.64 (m, 2H,
CH2OH), 3.71 (s, 3H, COOCH3), 3.86 (s, 3H, CH3O), 3.87 (s, 3H,
CH3O), 4.65 (d, J ) 10.0 Hz, 1H, H-11b), 5.28-5.29 (m, 1H, H-6),
6.58 (s, 1H, ArH), 6.64 (s, 1H, ArH); 13C NMR (100.6 MHz) δ
28.5 (C-2), 29.0 (C-7), 37.5 (C-1), 38.2 (C-3), 40.2 (CH2CO), 48.4
(C-6), 51.7 (CH3O2C), 52.9 (C-11b), 55.8 and 56.2 (CH3O), 62.1
(CH2OH), 108.3 and 111.8 (C-8 and C-11), 124.1 and 127.0 (C-7a
and C-11a), 147.8 and 148.1 (C-9 and C-10), 172.0 (COO); mp
148-151 °C (EtOAc-CHCl3); [R]22 +113.2 (c 0.34, CHCl3);
HMRS C19H25NO6, 363.1682; foundD, 363.1678.
(1R,2R,6S,11bR)-1-Ethyl-6-(hydroxymethyl)-9,10-dimethoxy-
2-(methoxycarbonylmethyl)-4-oxo-1,2,3,6,7,11b-hexahydroben-
zo[a]quinolizine (5d). Operating as in the above preparation of
5b, a solution of lactam 4d (163 mg, 0.42 mmol) and BF3·OEt2
(0.21 mL, 1.67 mmol) in CH2Cl2 (5 mL) was refluxed for 21 h.
Flash chromatography (9:1 EtOAc-MeOH) afforded 5d (66 mg,
1
40%): IR (film) 1637, 1733, 3000-3500 cm-1; H NMR (500
MHz) δ 0.92 (t, J ) 7.5 Hz, 3H, CH3), 1.40-1.47 (m, 1H, CH2-
CH3), 1.49-1.54 (m, 1H, H-1), 1.59-1.66 (m, 1H, CH2CH3), 2.28-
2.29 (m, 2H, CH2CO or H-3), 2.35 (dd, J ) 15.5, 3.0 Hz, 1H,
CH2CO or H-3), 2.44-2.49 (m, 1H, H-2), 2.67 (dd, J ) 15.5, 6.0
Hz, 1H, H-3), 2.70 (dd, J ) 15.5, 5.0 Hz, 1H, H-7), 2.76 (sa, 1H,
OH), 2.95 (dd, J ) 15.5, 5.5 Hz, 1H, H-7), 3.30-3.35 (m, 1H,
CH2OH), 3.45-3.48 (m, 1H, CH2OH), 3.63 (s, 3H, COOCH3), 3.84
(s, 3H, CH3O), 3.86 (s, 3H, CH3O), 4.22 (d, J ) 9,0 Hz, 1H, H-11b),
4.76-4.80 (m, 1H, H-6), 6.61 (s, 1H, ArH), 6.65 (s, 1H, ArH);
13C NMR (100.6 MHz) δ 10.7 (CH3), 24.7 (CH2CH3), 29.6 (C-7),
32.1 (C-2), 36.1 and 40.0 (C-3 and CH2CO), 46.0 (C-1), 51.6
(COOCH3), 51.7 (C-6), 55.9 and 56.2 (CH3O), 57.5 (C-11b), 64.7
(CH2OH), 111.0 and 112.0 (C-8 and C-11), 125.9 and 126.1 (C-7a
and C-11a), 147.2 and 148.5 (C-9 and C-10), 172.2 (C-4), 173.0
(COO); mp 116-118 °C (Et2O-acetone); [R]22 +53.3 (c 0.84,
CHCl3). Anal. Calcd for C21H29NO6: C, 64.43;DH, 7.47; N, 3.58.
Found: C, 64.07; H, 7.86; N, 3.65.
(1R,6S,11bR)-1-Ethyl-6-(hydroxymethyl)-9,10-dimethoxy-4-
oxo-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizine (5b). BF3·OEt2
(0.16 mL, 1.25 mmol) was added dropwise via syringe to a solution
of lactam 4b (99 mg, 0.31 mmol) in CH2Cl2 (3 mL), and the
resulting mixture was heated at reflux for 18 h. The solvent was
removed under reduced pressure, and the residue was dissolved in
EtOAc. The organic solution was washed with saturated aqueous
NaCl solution, the aqueous layer was extracted with EtOAc, and
(1R,6S,12bR)-1-Ethyl-6-(hydroxymethyl)-4-oxo-1,2,3,4,6,7,12,-
12b-octahydroindolo[2,3-a]quinolizine (9b). HCl (1.2 M) in EtOH
(4.1 mL) was added to a solution of lactam 8b (306 mg, 1.03 mmol)
J. Org. Chem, Vol. 72, No. 14, 2007 5199

Amat et al.
in EtOH (4.5 mL). The mixture was stirred at rt for 48 h. The
solvent was removed, and the resulting solid was diluted with
EtOAc and washed with saturated aqueous Na2CO3. After extraction
with EtOAc, the combined organic extracts were washed with H2O,
dried, and concentrated to give a residue, which was chromato-
graphed (1:1 EtOAc-hexane to EtOAc) to afford 9b (245 mg, 80%)
and its 12b-epimer 9b′ (40 mg, 13%). 9b: IR (film) 1614, 3000-
3500 cm-1; 1H NMR (400 MHz) δ 1.11 (t, J ) 7.2 Hz, 3H, CH3),
1.62-1.70 (m, 2H, CH2CH3, H-2), 1.85-1.92 (m, 2H, CH2CH3,
H-2), 2.01-2.06 (m, 1H, H-1), 2.35 (ddd, J ) 17.6, 6.5, 6.5 Hz,
1H, H-3), 2.52 (ddd, J ) 17.6, 6.5, 6.5 Hz, 1H, H-3), 2.63 (d, J )
16.0 Hz, 1H, H-7), 3.04 (ddd, J ) 16.0, 6.8, 2.4 Hz, 1H, H-7),
3.64-3.66 (m, 2H, CH2OH), 4.54 (d, J ) 6.4 Hz, 1H, H-12b),
5.45 (m, 1H, H-6), 7.10 (td, J ) 7.6, 0.8 Hz, 1H, ArH), 7.18 (td,
J ) 7.2, 0.8 Hz, 1H, ArH), 7.35 (d, J ) 8.0 Hz, 1H, ArH), 7.46 (d,
J ) 8.0 Hz, 1H, ArH), 8.13 (b s, 1H, NH); 13C NMR (100.6 MHz)
δ 11.5 (CH3), 21.4 (C-7), 22.8 and 26.1 (CH2CH3 and C-2), 30.4
(C-3), 38.9 (C-1), 49.7 (C-6), 54.2 (C-12b), 61.8 (CH2OH), 108.5
(C-7a), 111.0 (CH), 118.1 (CH), 119.8 (CH), 122.3 (CH), 127.1
(C-7b), 132.2 (C-12a), 136.0 (C-11a), 172.0 (C-4); mp 105 °C dec
(hexane-EtOAc); [R]2D2 +67.3 (c 0.5, CHCl3). Anal. Calcd for
C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.19; H, 7.39;
N, 9.24. 9b′: IR (film) 1616, 3000-3500 cm-1; 1H NMR (DMSO,
400 MHz) δ 0.85 (m, 4H, CH2CH3), 1.15 (m, 1H, CH2CH3), 1.41
(m, 1H, H-2), 2.12 (m, 1H, H-2), 2.25 (m, 1H, H-3), 2.41-2.62
(m, 3H, H-1, H-3, H-7), 2.90 (m, 1H, CH2OH), 3.14-3.23 (m,
2H, H-7, CH2OH), 4.62 (m, 1H, H-6), 4.84 (br s, 1H, OH), 4.87
(br s, 1H, H-12b), 6.97 (t, 1H, J ) 7.2 Hz, H-9), 7.05 (t, 1H, J )
7.2 Hz, H-10), 7.34 (d, 1H, J ) 7.6 Hz, H-11), 7.42 (d, 1H, J )
7.2 Hz, H-8), 10.92 (br s, 1H, NH); 13C NMR (DMSO, 100.6 MHz)
δ 11.6 (CH3), 19.8 (C-7), 22.7 (C-2), 23.3 (CH2CH3), 30.6 (C-3),
36.8 (C-1), 49.5 (C-6), 54.3 (C-12b), 61.5 (CH2OH), 106.2 (C-
7a), 111.4 (C-11), 118.0 (C-8), 118.7 (C-9), 121.0 (C-10), 127.1
(C-7b), 131.5 (C-12a), 136.8 (C-11a), 171.7 (C-4); mp 250-252 °C
(MeOH); [R]2D2 +81.7 (c 0.4, CH3OH). Anal. Calcd for
C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.27; H, 7.47;
N, 9.18.
9), 121.1 (C-10), 127.0 (C-7b), 135.8 (C-12a), 136.2 (C-11a), 172.1
(C-4); mp 203-204 °C; [R]2D2 -113.9 (c 0. 5, CH3OH). Anal.
Cald for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.34;
H, 7.40; N, 9.29.
(1R,4S,6S,12bS)-4,6-(Epoxymethano)-1-ethyl-1,2,3,4,6,7,12,-
12b-octahydroindolo[2,3-a]quinolizine (11). BF3·OEt2 (1.31 mL,
5 mmol) was added to a solution of lactam 8b (494 mg, 1.66 mmol)
in CH2Cl2 (19 mL), and the resulting mixture was heated at reflux
for 24 h. The solvent was evaporated under reduced pressure, the
residue (75.40 mg) was dissolved in MeOH (60 mL), NaBH4 (141
mg, 3.71 mmol) was added to the solution, and the mixture was
stirred for 40 min. The solvent was evaporated, and the resulting
residue was dissolved in EtOAc. The organic phase was washed
with H2O, dried, and concentrated, and the resulting residue was
chromatographed (EtOAc to EtOAc-MeOH 9:1) to afford 9b (65
1
mg, 13%) and 11 (338 mg, 73%). 11: IR (NaCl) 3313 cm-1; H
NMR (300 MHz) δ 0.82 (t, J ) 7.5 Hz, 3H, CH3), 1.15 (m, 1H,
CH2CH3), 1.52-1.68 (m, 3H, CH2CH3, H-2, H-1), 1.86-1.98 (m,
2H, H-1, H-3), 2.05 (m, 1H, H-2), 2.60 (ddd, J ) 15.3, 10.8, 2.4
Hz, 1H, H-6), 2.92-3.02 (m, 2H, H-5a, H-6), 3.72-3.77 (m, 2H,
H-5, H-3a), 3.88 (dd, J ) 9.0, 3.0 Hz, 1H, H-11b), 4.20 (t, J ) 7.2
Hz, 1H, H-5), 7.10 (td, J ) 7.2, 1.2 Hz, ArH), 7.15 (td, J ) 7.2,
1.2 Hz, 1H, ArH), 7.33 (dm, J ) 7.6 Hz, 1H, ArH), 7.47 (dd, J )
7.2, 1.5 Hz, 1H, ArH), 7.84 (br s, 1H, NH); 13C NMR (75.4.4 MHz)
δ 12.3 (CH3), 19.1 (CH2CH3), 24.3 (C-2), 25.0 (C-6), 26.1 (C-1),
37.9 (C-3), 57.5 (C-5a), 59.3 (C-11b), 71.2 (C-5), 92.6 (C-11b),
109.6 (C), 110.8 (CH), 117.9 (CH), 119.4 (CH), 121.4 (CH), 127.2
(C), 133.7 (C), 136.4 (C); MS-EI m/z 282 (M+, 35), 265 (18), 253
(20), 240 (51), 184 (46), 169 (78).
(1R,6S,12bS)-1-Ethyl-6-(hydroxymethyl)-1,2,3,4,6,7,12,12b-oc-
tahydroindolo[2,3-a]quinolizine (12). LiAlH4 (171 mg, 4.51
mmol) was added to a cooled (0 °C) solution of AlCl3 (182 mg,
1.37 mmol) in THF (14 mL), and the mixture was stirred at room
temperature for 30 min. The suspension was cooled (-78 °C), and
a solution of oxazolidine 11 (189 mg, 0.67 mmol) in THF was
added. The mixture was stirred at -78 °C for 90 min, warmed to
room temperature, and stirred for additional 2 h. Cold H2O was
added, and the mixture was extrated with CH2Cl2. The combined
organic extracts were dried and concentrated, and the resulting
residue was chromatographed to furnish 12 (127 mg, 69%): 1H
NMR (DMSO, 300 MHz) δ 0.75.4 (t, 3H, J ) 10.0 Hz, CH3),
0.81-0.96 (m, 1H, CH2CH3), 1.38-1.52 (m, 3H, H-2, H-3, CH2-
CH3), 1.59-1.80 (m, 2H, H-2, H-3), 2.06-2.13 (m, 2H, H-1, H-4),
2.30-2.38 (m, 1H, H-6), 2.43 (dd, 1H, J ) 14.7, 2.1 Hz, H-7),
2.65 (dd, 1H, J ) 14.7, 1.5 Hz, H-7), 3.20-3.42 (m, 2H, H-4,
H-12b), 3.54 (dd, 1H, J ) 15.2, 6.4 Hz, CH2OH), 3.68 (dd, 1H, J
) 15.2, 6.4 Hz, CH2OH), 4.52 (br s, 1H, OH), 6.91 (td, 1H, J )
6.9, 1.2 Hz, H-9), 6.98 (td, 1H, J ) 6.9, 1.2 Hz, H-10), 7.26 (d,
1H, J ) 10.4 Hz, H-11), 7.31 (d, 1H, J ) 10.0 Hz, H-8), 10.54 (s,
1H, NH); 13C NMR (DMSO, 75.4.4 MHz) δ 12.3 (CH3), 19.2 (CH2-
CH3), 21.1 (C-2), 25.8 (C-7), 26.0 (C-3), 38.3 (C-1), 51.0 (C-4),
62.1 (C-6), 63.7 (CH2OH), 64.7 (C-12b), 107.6 (C-7a), 111.0 (C-
11), 117.3 (C-8), 118.2 (C-9), 120.2 (C-10), 126.8 (C-7b), 134.9
(C-12a), 136.3 (C-11a).
(1R,6S,12bS)-1-Ethyl-6-(hydroxymethyl)-4-oxo-1,2,3,4,6,7,12,-
12b-octahydroindolo[2,3-a]quinolizine (9b′). BF3·OEt2 (2.7 mL,
10.3 mmol) was added to a solution of lactam 8b (1.02 g, 3.42
mmol) in CH2Cl2 (38 mL), and the resulting mixture was heated at
reflux for 24 h. The solvent was evaporated under reduced pressure,
and the residue was dissolved in EtOAc. The organic solution was
washed with saturated aqueous NaCl, the aqueous layer was
extracted with EtOAc, and the combined organic extracts were dried
and concentrated. The resulting residue was dissolved in CH2Cl2
and stirred for 18 h in the presence of KOH (710 mg). H2O was
added to the mixture, the organic phase was separated, and the
aqueous phase was extrated with EtOAc. The combined organic
extracts were dried and concentrated, and the resulting residue was
digested with CH2Cl2 to yield a precipitate, which was filtered and
recrystallized in EtOH to afford 9b′ (0.62 g, 61%). The previous
filtrate was concentrated, and the resulting residue was chromato-
graphed (hexane-EtOAc 1:4 to EtOAc-MeOH 9:1) to afford 9b
(0.13 mg, 13%). Ocasionally, minor amounts of 1-epi-9b′ were
(1R,2R,6S,12bR)-1-Ethyl-6-(hydroxymethyl)-2-(methoxycar-
bonylmethyl)-4 -oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-
quinolizine (9d). HCl (6.5 M) in MeOH (1 mL) was added to a
solution of lactam 8d (133 mg, 0.36 mmol) in MeOH (3 mL). The
mixture was stirred at room temperature for 25 h. The solvent was
removed, and the resulting solid was diluted with EtOAc and
washed with saturated aqueous Na2CO3. After extraction with
EtOAc, the combined organic extracts were washed with H2O,
dried, and concentrated to give a residue, which was chromato-
graphed (Et2O) to afford 9d (64 mg, 48%) and its C-1 epimer 9d′
isolated in the chromatography: IR (film) 1621, 3000-3500 cm-1
;
1H NMR (DMSO, 400 MHz) δ 1.04 (t, 3H, J ) 7.2 Hz, CH3CH2),
1.48-1.65 (m, 3H, CH3CH2, H-2), 1.75.4 (m, 1H, CH3CH2), 1.95
(m, 1H, H-3), 2.30-2.39 (m, 2H, H-1, H-3), 2.71 (1H, ddd, J )
15.2, 3.6, 1.2 Hz, H-7), 2.96 (ddd, 1H, J ) 15.2, 11.2, 2.0 Hz,
H-7), 3.45 (m, 1H, H-6), 3.84 (ddd, 1H, J ) 10.8, 6.4, 4.0 Hz,
CH2OH), 4.00 (ddd, 1H, J ) 10.8, 6.0, 6.0 Hz, CH2OH), 4.69 (br
s, 1H, H-12b), 4.98 (m, 1H, OH), 6.96 (td, 1H, J ) 7.2, 0.8 Hz,
H-9), 7.04 (td, 1H, J ) 7.2, 1.2 Hz, H-10), 7.32 (d, 1H, J ) 8.0
1
(39 mg, 29%). 9d: IR (KBr) 1619, 1733, 3000-3500 cm-1; H
Hz, H-11), 7.37 (d, 1H, J ) 7.6 Hz, H-8), 10.82 (s, 1H, NH); 13
C
NMR (CDCl3, 500 MHz) δ 1.12 (t, J ) 7.5 Hz, 3H, CH3), 1.67-
1.74 (m, 1H, CH2CH3), 1.80 (m, 1H, CH2CH3), 1.91 (br s, 1H,
OH), 2.12 (m, 1H, H-1), 2.21 (d, J ) 7.5 Hz, 2H, COOCH2), 2.33
(ddd, J ) 17.0, 3.5, 1.0 Hz, 1H, H-3), 2.45 (m, 1H, H-2), 2.69 (dd,
NMR (DMSO, 100.6 MHz) δ 12.0 (CH3), 21.8 (C-2), 22.8 (C-7),
23.8 (CH2CH3), 29.5 (C-3), 35.8 (C-1), 62.0 (C-12b), 63.3 (C-6),
63.4 (CH2OH), 109.5 (C-7a), 111.5 (C-11), 117.7 (C-8), 118.8 (C-
5200 J. Org. Chem., Vol. 72, No. 14, 2007

Synthesis of Benzo[a]- and Indolo[2,3-a]quinolizidines
J ) 16.0, 2.5 Hz, 1H, H-7), 2.70 (dd, J ) 17.0, 6.0 Hz, 1H, H-3),
3.01 (ddd, J ) 16.0, 6.5, 2.5 Hz, 1H, H-7), 3.52 (s, 3H, CH3O),
3.57 (t, J ) 11.5 Hz, 1H, CH2OH), 3.67 (dd, J ) 11.5, 6.0 Hz, 1H,
CH2OH), 4.59 (m, 1H, H-12b), 5.41 (ddd, J ) 10.0, 6.0, 6.0 Hz,
1H, H-6), 7.11 (td, J ) 7.5, 1.0 Hz, 1H, ArH), 7.17 (td, J ) 7.5,
1.0 Hz, 1H, ArH), 7.32 (d, J ) 7.5 Hz, 1H, ArH), 7.46 (d, J ) 7.5
Hz, 1H, ArH), 7.95 (br s, 1H, NH); 13C NMR (CDCl3, 100.6 MHz)
δ 11.6 (CH3), 21.4 (CH2CH3), 26.6 (CH2CH3), 31.3 (C-2), 34.8
(C-3), 38.1 (CH2COO), 42.3 (C-1), 49.6 (C-6), 51.6 (CH3O), 52.6
(C-12b), 62.5 (CH2OH), 107.5 (C-7a), 111.0 (C-11), 118.3 (C-8),
120.0 (C-9), 122.4 (C-10), 127.3 (C-7b), 132.1 (C-12a), 136.1
(C-11a), 170.8 (C-4), 172.6 (COO); mp 203-204 °C; [R]2D2 +32.1
(c 0.32, CHCl3). Anal. Calcd for C21H26N2O4: C, 68.09; H, 7.07;
N, 7.56. Found: C, 68.24, H, 7.32, N, 7.56. 9d′: IR (KBr) 1618,
CH2COO), 38.7 (C-1), 50.0 (C-6), 51.5 (C-12b), 51.8 (CH3O),
61.6 (CH2OH), 109.4 (C-7a), 111.4 (C-11), 118.0 (C-8), 119.8
(C-9), 122.2 (C-10), 127.6 (C-7b), 132.6 (C-12a), 136.0 (C-11a),
172.8 (COO); MS-EI m/z 370 (M+, 10), 339 (42), 242 (27), 169
(65).
Acknowledgment. Financial support from the Ministry of
Science and Technology (Spain)-FEDER (Projects BQU2003-
00505 and CTQ2006-02390/BQU) and the DURSI, Generalitat
de Catalunya (Grant 2005SGR-0603), is gratefully acknowl-
edged. Thanks are also due to the Ministry of Education, Culture
and Sport (Spain) for a fellowship to O.B. and the Fundac¸a˜o
para a Cieˆncia e Tecnologia (Lisbon, Portugal) for a postdoctoral
Grant to M.M.M.S.
1731, 3000-3500 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.13
;
(t, J ) 7.6 Hz, 3H, CH3CH2), 1.55-1.62 (m, 2H, CH3CH2), 2.30-
2.43 (m, 6H, H-1, H-2, H-3, CH2COO), 2.52 (d, J ) 16.0 Hz, 1H,
H-7), 3.14 (ddd, J ) 16.0, 7.2, 2.0 Hz, 1H, H-7), 3.70 (s, 3H,
CH3O), 3.73 (dd, J ) 8.0, 1.6 Hz, 1H, CH2OH), 3.78 (d, J ) 8.0
Hz, 1H, CH2OH), 4.78 (br s, 1H, H-12b), 5.40 (m, 1H, H-6), 7.11
(t, J ) 7.2 Hz, 1H, H-9), 7.18 (t, J ) 7.6 Hz, 1H, H-10), 7.39
(d, J ) 8.0 Hz, 1H, H-11), 7.44 (d, J ) 8.0 Hz, 1H, H-8), 8.38
(br s, 1H, NH); 13C NMR (CDCl3, 100.6 MHz) δ 12.7 (CH3CH2),
18.3 (CH3CH2), 21.5 (C-7), 29.2 (C-2), 34.9 and 35.0 (C-3,
Supporting Information Available: Experimental procedures
for the HCl-promoted cyclization of lactams 4b-d and for the
conversions 5c f 7, 9b f 10, and 8b′ f 1-epi-9b, copies of the
1H and 13C NMR spectra of all new compounds, and X-ray
crystallographic data for compounds 4c, 4c′, 5b, 5d, 8e, 9b′, 1-epi-
9b, 1-epi-9b′, and 9d. This material is available free or charge via
the Internet at http://pubs.acs.org.
JO070539G
J. Org. Chem, Vol. 72, No. 14, 2007 5201