Conjugate additions of sulfur-stabilized anions to unsaturated lactams. Synthesis of polyfunctionalized benzo[a]quinolizinone systems

Article abstract of DOI:10.1021/jo060903w

Conjugate addition reactions of sulfur-stabilized nucleophiles to the δ-lactam unit of tetrahydrobenzo[a]benzoquinolizines have been studied. The stereochemical outcome of the conjugate addition reaction depends on the nature of the substituent at the ang

Full text of DOI:10.1021/jo060903w

Conjugate Additions of Sulfur-Stabilized Anions to Unsaturated
Lactams. Synthesis of Polyfunctionalized Benzo[a]quinolizinone
Systems
Eva Garc´ıa, Esther Lete,* and Nuria Sotomayor
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, UniVersidad del Pa´ıs Vasco/
Euskal Herriko Unibertsitatea, Apdo. 644, 48080 Bilbao, Spain
esther.lete@ehu.es
ReceiVed May 2, 2006
Conjugate addition reactions of sulfur-stabilized nucleophiles to the δ-lactam unit of tetrahydrobenzo-
[a]benzoquinolizines have been studied. The stereochemical outcome of the conjugate addition reaction
depends on the nature of the substituent at the angular position, thus 2,11b-cis or 2,11b-trans diastereomers
could be obtained selectively. The tandem conjugate addition-alkylation also takes place in good yields
and with high diastereoselectivity. The polyfunctionalized hexahydrobenzo[a]quinolizinone systems
obtained could be further elaborated toward emetine-like structures.
Introduction
associated with many of these drugs,6 much attention is still
directed toward the synthesis of natural or synthetic congeners
to study structure-activity relationships.7
During the past several years, research in our laboratories
has focused on the application of aromatic metalation and
R-amidoalkylation reactions for the synthesis of benzo-fused
indolizidine and quinolizidine compounds.8 Thus, we have
developed an approach for the construction of the benzo[a]-
quinolizidone skeleton that involves the Parham9 or N-acylimin-
ium ion10 cyclization as the key ring-forming step.8a The
The benzo[a]quinolizidine ring system is of considerable
interest and significance because this heterocyclic template is
found within a plethora of isoquinoline alkaloids, including
Ipecac alkaloids such as emetine and related bases, which
possess multifold interesting biological activity.1 For instance,
emetine shows antiamoebic properties,2 shows activity against
breast tumor cells,3 and can be used as an emetic.4 In a recent
work on novel classes of anticancer drugs, an extensive analysis
of various analogues of the original inhibitors allowed the
identification of a common structure that is essential for the
inhibition of Hsp induction (i.e., the 2H-benzo[a]quinolizidine
tricyclic system).5 Because of the toxicological problems
(5) Zaarur, N.; Gabai, V. L.; Porco, J. A., Jr.; Claderwood, S.; Sherman,
M. Y. Cancer Res. 2006, 66, 1783-1791.
(6) For a review on cardiotoxicity of emetine and analogues, see:
Stephen, P. M. Prin. Card. Toxicol. 1991, 331-346.
(7) For recent examples on the synthesis of emetine and related bases,
see: (a) Tietze, L. F.; Rackelmann, N.; Sekar, G. Angew. Chem., Int. Ed.
2003, 42, 4254-4257. (b) Tietze, L. F.; Rackelmann, N.; Mu¨ller, I. Chem.-
Eur. J. 2004, 10, 2722-2731. (c) Itoh, T.; Miyazaki, M.; Fukuoka, H.;
Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1295-1297.
(8) For representative examples of our synthetic work in this area, see:
(a) Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M. J.; Lete, E. J.
Org. Chem. 1997, 62, 2080-2092. (b) Osante, I.; Collado, M. I.; Lete, E.;
Sotomayor, N. Eur. J. Org. Chem. 2001, 1267-1277. (c) Ruiz, J.;
Sotomayor, N.; Lete, E. Org. Lett. 2003, 5, 1115-117. (d) Osante, I.; Lete,
E.; Sotomayor, N. Tetrahedron Lett. 2004, 45, 1253-1256. (e) Gonza´lez-
Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69,
3875-3885. (f) Ruiz, J.; Ardeo, A.; Ignacio, R.; Sotomayor, N.; Lete, E.
Tetrahedron 2005, 61, 3311-3324. (g) Garc´ıa, E.; Arrasate, S.; Lete, E.;
Sotomayor, N. J. Org. Chem. 2005, 70, 10368-10374.
* To whom correspondence should be addressed. Telephone: 34 94 6012576.
Fax: 34 94 6012748.
(1) Fujii, T.; Ohba, M. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol. 51, pp 271-323.
(2) Bansal, D.; Sehgal, R.; Cawla, Y.; Mahajan, R. C.; Malla, N. Ann.
Clin. Microb. Antimicrob. 2004, 3, 27. http://www.ann-clinmicrob.com/
content/3/27.
(3) Zhou, Y.-D.; Kim, Y.-P.-; Mohammed, K. A.; Jones, D. K.;
Muhammad, I.; Dunbar, D. C.; Nagle, D. G. J. Nat. Prod. 2005, 68, 847-
950.
(4) (a) Endo, T.; Nemoto, M.; Ogawa, T.; Tamakai, H.; Hamaue, N.;
Hirafuji, M.; Takeda, Y.; Hasegawa, M.; Fujii, Y.; Minami, M. Res.
Commun. Mol. Pathol. Pharmacol. 2000, 108, 187-200. (b) Lin, T.-H.
U.S. Patent Appl. 2005, 0220715.
10.1021/jo060903w CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006
6776
J. Org. Chem. 2006, 71, 6776-6784

Synthesis of Polyfunctionalized Benzo[a]quinolizinones
presence of the R,â-unsaturated lactam unit in benzo[a]-
quinolizidones would allow for possible further functionalization
en route to natural products or more complex targets. We
envisaged the conjugate system could be generated by oxidative
elimination via selenoxides,11 obtained from the corresponding
selenides. Therefore, benzo[a]quinolizidones would represent
late-stage intermediates in the stereocontrolled synthesis of
Ipecac alkaloid analogues by a conjugate addition reaction.
FIGURE 1. Tandem conjugate addition-electrophile trap on benzo-
quinolizidones.
The conjugate addition of various organometallic reagents
to R,â-unsaturated carbonyl compounds is an important process
for carbon-carbon bond formation in organic synthesis.12
Although compared with some other classes of conjugate
acceptors R,â-unsaturated amides and lactams are usually less
reactive, it is known that sulfur-stabilized anions do not need
the presence of an activating group attached to the unsaturated
system to give regioselectively 1,4-addition. Thus, several
authors have demonstrated that lithiated 1,3-dithianes undergo
conjugate addition to tertiary crotonamides, thioamides, and
lactams. The resulting amide enolates may be quenched with
electrophiles to give R,â-dialkylated products.13 These R-lithiodi-
thioacetals are particularly useful acyl anion equivalents because
they provide an umpolung to the normal reactivity pattern of
carbonyl compounds.14 In this context, we have previously
shown that highly diastereoselective conjugate addition of
R-lithiodithioacetals to the R,â-unsaturated bicyclic lactam unit
of dihydropyrrolo[2,1-a]isoquinolones can be achieved. Cis or
trans 1,10b-disubstituted isomers could be obtained exclusively
by using a 1,3-dithianyl anion or bis(phenylthio)methyllithium
as nucleophiles, respectively.15 With these precedents, we
decided to study the conjugate additions of sulfur-stabilized
anions to the R,â-unsaturated lactam moiety of benzoquinolizi-
dones (Figure 1), paying special attention to the effect of both
the nucleophile and the substitution on C-11b (R1 ) H, Me) on
the stereoselectivity. To show the synthetic potential of these
conjugate additions, the adducts would be further manipulated
to access various polyfunctionalized benzo[a]quinolizidones.16
Results and Discussion
Our first task was the synthesis of benzoquinolizidones 3a,b,
which incorporate different substituents on C-11b. The benzo-
quinolizinone skeleton was assembled through R-amidoalkyla-
tion reactions of glutarimide 1. The addition of organolithium
reagents and the reduction of imides are efficient methods to
access R-hydroxylactams, immediate precursors of N-acylimin-
ium ions, which have been successfully used to access various
types of isoquinoline skeletons.8 Thus, treatment of glutarimide
1 with NaBH4 under the conditions reported by Speckamp17
yielded a mixture of tautomeric R-hydroxylactam and oxoamide,
which, without purification, were cyclized with TFA to give
2a in good overall yield (Scheme 1).18 Similarly, treatment of
1 with MeLi (3 equiv) yielded an oxoamide that was cyclized
to afford 2b in similar overall yield. The double bond was
introduced then by an oxidative elimination of a selenoxide.
Thus, deprotonation with LDA, followed by treatment with
PhSeBr, afforded the corresponding diastereomeric selenides.
The oxidative elimination was carried out with H2O2 to afford
3b. However, when these conditions were applied to the
(9) For reviews on Parham-type cyclizations, see: (a) Parham, W. E.;
Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300-305. (b) Wakefield, B. J.
The Chemistry of Organolithium Compounds, 2nd ed.; Pergamon Pres: New
York, 1990. (c) Gray, M.; Tinkl, M.; Snieckus, V. In ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon Press: Exeter, 1995; Vol. 11, pp 66-92. (d) Ardeo, A.;
Collado, M. I.; Osante, I.; Ruiz, J.; Sotomayor, N.; Lete, E. In Targets in
Heterocyclic Systems; Atanassi, O., Spinelli, D., Eds.; Italian Society of
Chemistry: Rome, 2001; Vol. 5, pp 393-418. (e) Mealy, M. J.; Bailey,
W. F. J. Organomet. Chem. 2002, 646, 59-67. (f) Clayden, J. Organo-
lithiums: SelectiVity for Synthesis; Pergamon Press: New York, 2002. (g)
Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275-300. (h) Na´jera,
C.; Sansano, J. M.; Yus, M. Tetrahedron 2003, 59, 9255-9303. (i)
Rappoport, Z.; Marek, I.; In The Chemistry of Organolithium Compounds;
Rappoport, Z.; Ed.; Patai Series: The Chemistry of Functional Groups;
Wiley: Chichester, 2004. (j) Arrasate, S.; Sotomayor, N.; Lete, E. In New
Methods for the Asymmetric Synthesis of Nitrogen Heterocycles; Vicario,
J. L., Bad´ıa, D., Carrillo, L., Eds.; Research Signpost: India, 2005; pp 223-
248.
(10) For reviews on N-acyliminium ion chemistry, see: (a) Speckamp,
W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (b) Hiemstra, H.;
Speckamp, W. N. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1988; Vol. 32, pp 271-339. (c) Hiemstra, H.; Speckamp, W. N. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, pp 1047-1082. (d) de Koning, H.; Speckamp,
W. N. In StereoselectiVe Synthesis [Houben-Weyl], Workbench ed. E21;
Helmchen, G., Hoffmann, R. W., Muzler, J., Schaumann, E., Eds.;
Thieme: Stuttgart, 1996; Vol. 3, pp 1952-2010. (e) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856. (f) Royer, J.; Bonin,
M.; Micouin, L. Chem. ReV. 2004, 104, 2311-2352. (g) Maryanoff, B. E.;
Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV.
2004, 104, 1431-1628. (h) Dobbs, A. P.; Rossiter, S. In ComprehensiVe
Organic Functional Group Transformations II; Katritzky, A. R., Taylor,
R. J. K., Eds.; Elsevier: Oxford, 2005; Vol. 3, pp 419-450.
(13) (a) Tamaru, Y.; Harada, T.; Iwawoto, H.; Yoshida, Z.-I. J. Am.
Chem. Soc. 1978, 100, 5221-5223. (b) Mpango, G. B.; Mahalanabis, K.
K.; Damghani, Z. M.; Snieckus, V. Tetrahedron Lett. 1980, 21, 4823-
4826. (c) Mpango, G. B.; Snieckus, V. Tetrahedron Lett. 1980, 21, 4827-
4830. (d) Hashimoto, M.; Hashimoto, K.; Shirahama, H. Tetrahedron 1996,
52, 1931-1943. (e) Forns, P.; D´ıez, A.; Rubiralta, M. Tetrahedron 1996,
52, 3563-3574. (f) Forns, P.; D´ıez, A.; Rubiralta, M. J. Org. Chem. 1996,
61, 7882-7888. (g) Amat, M.; Pe´rez, P.; Llor, N.; Bosch, J. Org. Lett.
2002, 4, 2787-2790.
(14) For reviews on synthetic uses of R-lithiodithioacetals, see: (a)
Seebach, D. Synthesis 1969, 1, 17-36. (b) Krief, A. Tetrahedron 1980,
36, 2531-2640. (c) Page, P. C. B.; van Niel, M. B.; Prodger, J. C.
Tetrahedron 1989, 45, 7643-7677. (d) Yus, M.; Na´jera, C.; Foubelo, F.
Tetrahedron 2003, 59, 6147-6212.
(15) Etxarri, B.; Gonza´lez-Temprano, I.; Manteca, I.; Sotomayor, N.;
Lete, E. Synlett 1999, 1486-1488.
(16) This work was presented in part at the 7th International Symposium
on Carbanion Chemistry (ISCC-7), Alicante, Spain, July 7-11, 2004. See
book of abstracts: communication P-39.
(17) Speckamp, W. N.; Hubert, J. C.; Stege, W.; Huisman, H. O. Synth.
Commun. 1971, 1, 103-109.
(18) When the reaction was carried out in a larger scale (3 g of 1), it
was not possible to control the partial reduction of the imide, and N-(3,4-
dimethoxyphenylethyl)-4-hydroxybutyramide was obtained. This hydroxya-
mide could be oxidized (Swern) to the aldehyde and cyclized with TFA to
afford 3a in good overall yield. See Supporting Information.
(11) Manteca, I.; Etxarri, B.; Ardeo, A.; Arrasate, S.; Osante, I.;
Sotomayor, N.; Lete, E. Tetrahedron 1998, 54, 12361-12378 and references
therein.
(12) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Baldwin, J. E., Magnus, P. D., Eds.; Tetrahedron Organic Chemistry
Series; Pergamon Press: Oxford, 1992; Vol. 9. (b) Rossiter, B. E.; Swingle,
N. M. Chem. ReV. 1992, 92, 771-806. (c) Leonard, J.; D´ıez-Barra, E.;
Merino, S. Eur. J. Org. Chem. 1998, 2051-2061. (d) Yamamguchi, M. In
ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, pp 1121-1139. (e)
Iguchi, M.; Yamada, K.; Tomioka, K. In Organolithiums in EnantioselectiVe
Synthesis; Hodgson, D. M., Ed.; Topics in Organometallic Chemistry;
Springer: Berlin, 2003; Vol. 5, pp 21-36.
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Garc´ıa et al.
TABLE 1. Conjugate Additions of Stabilized Anions to 3a,b
SCHEME 1a
a Reagents: (a) NaBH4, EtOH/H2O, HCl, 0 °C (for 2a); MeLi, -78 °C
(for 2b). (b) TFA, CH2Cl2, rt. (c) LDA, -78 °C, PhSeBr. (d) PIDA, TFA,
CH3CN/H2O, rt (for 3a); H2O2, pyridine, 0 °C f rt (for 3b).
SCHEME 2a
a Cyclopropane derivative 8 (Figure 2) was isolated as the major product
(68%).
FIGURE 2. Structure of byproduct 8.
temperatures from -78 °C to room temperature. Optimization
of the reaction conditions revealed that 1,4-addition occurred
when the anion was prepared at -78 °C, allowed to reach room
temperature, and quenched by addition of the lactam 3a or 3b
(Table 1).
However, in the case of 3a, if the reaction mixture was stirred
overnight (entry 1), the addition product 5a was isolated in low
yield (5%) and the major compound was the cyclopropane
derivative 8 (Figure 2).21 The formation of 8 could be explained
by nucleophilic displacement of a thiophenyl group by the
enolate formed after the conjugate addition reaction.22 Thus, a
reduction of the reaction time (entry 2) allowed the isolation of
the cis diastereomer 5a in good yield and with complete
diastereoselectivity. These conditions were applied to the
addition of 2-lithio-1,3-dithiane (entry 3), obtaining the corre-
sponding cis adduct 5b as a single diastereomer in high yield.
Interestingly, a reversal of the stereoselectivity was observed
a Reagents: (a) (R2S)2CHLi, -78 °C, 1 h.
diastereomeric selenides derived from 2a, only low yields of
3a were obtained (10%). In this case, the oxidative elimination
was finally carried out successfully with PIDA (phenyliodonium
diacetate). Although this type of hypervalent iodine reagent is
well-known and has been extensively used in organic synthe-
sis,19 to our knowledge, it had not been used previously for
this type of selenoxide elimination.
Then, we studied the conjugate addition reactions of
R-lithiodithioacetals to unsaturated bicyclic δ-lactams 3a and
3b. For this purpose, we chose 2-lithio-1,3-dithiane and bis-
(phenylthio)methyllithium, which could show different behavior
in conjugate additions.15 The latter anion would be more stable,
whereas its acyclic structure allows rotation, optimizing orbital
overlap with the conjugate acceptor.20 First, we studied the
addition of bis(phenylthio)methyllithium to lactams 3a,b (Scheme
2, Table 1). The anion could be efficiently prepared by
deprotonation of bis(phenylthio)methane with n-BuLi at -78
°C for 1 h. However, no reaction was observed if the conjugate
acceptor was added at this temperature and allowed to reach
(21) COSY, HMQC, and NOESY experiments were used to confirm the
structure of 8. The value of the coupling constant among the cyclopropane
protons and the NOE enhancement between H-11b and the PhSCH were
consistent with the stereochemistry shown in the figure.
(19) For reviews, see: (a) Tohma, H.; Kita, Y. Top. Curr. Chem. 2003,
224, 209-248. (b) Moreno, I.; Tellitu, I.; Herrero, M. T.; SanMart´ın, R.;
Dom´ınguez, E. Curr. Org. Chem. 2002, 6, 1433-1452. (c) Pelter, A.; Ward,
R. S. Tetrahedron 2001, 57, 273-282. For some recent examples, see: (d)
Felim, A.; Toussaint, A.; Phillips, C. R.; Leca, D.; Vagstad, A.; Fensterbank,
L.; Lacote, E.; Malacria, M. Org. Lett. 2006, 8, 337-339. (e) Herrerias, C.
I.; Zhang, T. Y.; Li, C.-J. Tetrahedron Lett. 2006, 47, 13-17.
(20) (a) Ager, D. J.; East, M. B. J. Org. Chem. 1986, 51, 3983-3992.
(b) Schreiber, S. L. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1992; Vol. 1, Part 1.
(22) The formation of this type of cyclopropane derivatives has been
previously reported in the conjugate addition of this sulfur-stabilized
carbanion to cyclohexenone. See: (a) Cohen, T.; Yu, L.-C. J. Org. Chem.
1985, 50, 3266. (b) Cohen, T.; Myers, M. J. Org. Chem. 1988, 53, 457.
6778 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of Polyfunctionalized Benzo[a]quinolizinones
SCHEME 3a
a Reagents: (a) (R2S)2CHLi, -78 °C, 1 h, f rt, 5 h; EtI, rt, 12 h.
TABLE 2. Conjugate Addition-Electrophile Trap Reactions of
3a,b
FIGURE 3. Stereochemical outcome of the conjugate addition.
when the C-11b substituted lactam 3b was used as substrate.
As shown in Table 1, the trans adducts 6a and 6b were the
major compounds formed when 3b was treated with both bis-
(phenylthio)methyllithium and 2-lithio-1,3-dithiane, with reason-
able diastereoselectivities (entries 4-6). Shorter reaction times
did not significantly effect the diastereoselectivity (entry 6).
Thus, benzo[a]quinolizinones 3a and 3b undergo conjugate
addition of sulfur-stabilized anions with opposite facial selectiv-
ity. These results are in agreement with those obtained by Amat
and Bosch,23 who have studied the factors governing the facial
stereoselectivity observed in the conjugate addition of several
types of nucleophiles to phenylglycinol-derived unsaturated
bicyclic δ-lactams. Similar effects have also been described by
Allin24 for the conjugate addition reactions on indolo[2,3-a]-
quinolizine systems. It should be noted that, in the cases
described by these authors, the angular substituent R to the
nitrogen atom is always a hydrogen atom, and we have studied
the effect of a methyl substituent at this position. Thus, in our
case, when R ) H, attack of the nucleophile to these confor-
mationally rigid lactams occurs under stereoelectronic control,
parallel with respect to the axial hydrogen in C-11b (exo
attack).25 This leads to a 1,3-syn disposition of both substituents
in the resulting intermediate A (Figure 3). However, when the
axial hydrogen is replaced by a methyl group, this 1,3-syn
diaxial interaction in the resulting intermediate or in the
transition state leading to it would favor an antiparallel attack
leading to the more stable trans diastereomer through an
intermediate such as B.
a 10a was isolated as a mixture of C-3 epimers (Figure 4). b 6b was
isolated as a byproduct.
FIGURE 4. Structure of epimeric products 10a and 10a′.
addition of bis(phenylthio)methyllithium, as the product was
isolated as an epimeric mixture of 10a and 10a′ in a 4:1 ratio
(Figure 4). On the other hand, the tandem addition-ethyl iodide
trap on 3b yielded the corresponding trans products 11a and
11b as the major compounds (entries 3 and 4). These results
could be explained by assuming that in the enolates derived
from 3a both the hydrogen on C-11b and the dithioacetal group
are in pseudoaxial disposition. Consequently, steric factors
associated with the size of the substituents may bock the parallel
approach of the electrophile. In the alkylation of the enolates
derived from 3b, with a pseudoaxial methyl group on C-11b
and a pseudoequatorial dithioacetal on C-2, approach of the
electrophile always takes place opposite to the dithioacetal
group.
We next studied the feasibility of performing a tandem
conjugate addition-electrophile trap reaction on these substrates.
For this purpose, we chose ethyl iodide as the electrophile. As
shown before, the addition of both sulfur-stabilized anions to
3a was completely syn selective, obtaining the adducts 10a and
10b (Scheme 3, Table 2, entries 1 and 2). However, enolate
alkylation was not completely stereoselective in the case of the
(23) (a) Amat, M.; Pe´rez, M.; Minaglia, A. T.; Casamitjana, N.; Bosch,
J. Org. Lett. 2005, 7, 3653-3656. (b) Amat, M.; Pe´rez, M.; Llor, N.;
Escolano, C.; Luque, F. J.; Molins, E.; Bosch, J. J. Org. Chem. 2004, 69,
8681-8693 and references therein.
(24) Allin, S. M.; Khera, J. S.; Thomas, C. I.; Witherington, J.; Doyle,
K.; Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2006, 47, 1961-1964.
(25) See, ref 12a, p 25.
NOESY and COSY experiments confirmed the stereochem-
istry of all the benzoquinolizinone derivatives. The most
significant results obtained with diastereomeric benzoquinoliz-
inone (2RS,11bRS)-6a and (2SR,11bRS)-7a are shown in Figure
5. Thus, for (2RS,11bRS)-6a, the J values of the ABX system
J. Org. Chem, Vol. 71, No. 18, 2006 6779

Garc´ıa et al.
Yield (%)
TABLE 3. Deprotection of Thioacetals
Entry
Substrate
Product
1
2
2
3
4
5a
5a
6a
13 + 14
14b
70a
80
80
80
70
15b
6b
15b
10ac
16b,c
a Diastereomeric ratio 13/14 2:1. b pH was maintained as acidic (pH )
6). c 4:1 epimeric mixture at C-3.
SCHEME 4a
FIGURE 5. Selected NOE enhancements for 5a, 5b, 6a, and 7a.
FIGURE 6. Selected NOE enhancements for 10b and 11b.
formed by H-2 and H-3 protons indicate that H-2 is in a
pseudoaxial position. Additionally, 2D NOE experiments showed
a Reagents: (a) PIDA, TFA, CH3CN/H2O, rt.
an enhancement between the methyl groups on C-11b, H-6axial
,
and H-2. Besides, no NOE was observed between the methyl
group on C-11b and the protons of the (PhS)2CH group. These
data are consistent with the preferred half-chair and half-boat
conformation for the quinolizidine system in which the sub-
stituents in C-11b and C-2 are in pseudoaxial and pseudoequa-
torial positions, respectively. Thus, the configuration was
assigned as 2RS,11bRS. On the other hand, for the cis-7a
diastereomer, the J values of the ABX system formed by H-2
and H-1 protons indicate that H-2 is also in a pseudoaxial
position. In this case, the absence of a NOE enhancement
between the methyl protons on C-11b and H-2 and the
enhancement observed between these methyl protons and the
phenyl protons of the thiophenyl rings confirmed that both
substituents are in a cis disposition, resulting from a 2SR,11bRS
configuration. Similar results were observed for benzoquino-
lizines 5a and 5b (see Figure 5). Thus, in both cases, no NOE
was observed between H-2 and H-11b, but the signal of the
aliphatic methine proton of the (PhS)2CH group was enhanced
when H-11b was irradiated and vice versa.
At this point, it was necessary to show that the masked
carbonyl groups could be easily deprotected. However, we tried
some of the most common deprotecting agents for this trans-
formation,26 always recovering the unreacted thioacetals. In view
of the good results obtained in the oxidation of selenides, we
decided to test PIDA as a deprotecting agent.27 As shown in
Table 3 and Scheme 4, selected thioacetals were smoothly
deprotected by treatment with PIDA and TFA in CH3CN/H2O.
Thus, when 5a was treated with PIDA and the reaction mixture
was basified with NaHCO3 during workup, a mixture of
aldehydes 13 and 14 was obtained in a 2:1 ratio (entry 1).
However, by simply maintaining an acidic medium throughout
the workup and purification procedures, this epimerization could
be prevented. Under these conditions, aldehydes 15 and 16 were
obtained in good yields.
To show the synthetic interest of these reactions, we chose
one of the aldehydes to further elaborate the structure toward
emetine analogues. Thus, aldehyde 15 was reduced to the
In the same way, the stereochemistry of trisubstituted
benzoquinolizidines was determined. As an example, selected
NOE enhancements for 11b and 10b are shown in Figure 6.
Thus, for (2RS,3SR,11bRS)-11b, a NOE enhancement between
the methyl protons on C-11b, H-2, and the ethyl group was
observed. On the other hand, the (2SR,3RS,11bRS)-10b dias-
tereomer showed a NOE enhancement between the H-11b atom
and the substituent at C-2 and H-3, whereas no NOE was
observed between the H-11b atom and the ethyl group (see
Figure 5). The rest of the NOE experiments carried out were
fully consistent with the proposed stereochemistry in each case.
(26) (a) HgO/BF3: see ref 15. (b) NaNO2/AcCl/H2O: Khan, A. T.;
Mondal, E.; Sahu, P. R. Synlett 2003, 377-381. (c) DMSO, 160 °C: Rao,
C. S.; Chandrasekharan, M.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1992,
33, 8163-8164. (d) NaHCO3/I2: Desroy, N.; Le Roux, R.; Phansavath, P.;
Chiummiento, L.; Bonini, C.; Geˆnet, J.-P. Tetrahedron Lett. 2003, 44, 1763-
1766. (e) NaHCO3/MeI: Takai, S.; Sawada, N.; Isobe, M. J. Org. Chem.
2003, 68, 3225-3231.
(27) Hypervalent iodine compounds such as PIFA [phenyliodine(III) bis-
(trifluoroacetate)] have been reported to oxidize sulfur-containing com-
pounds. See, for instance: (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989,
30, 287-290. (b) Birk, C.; Voss, J. Tetrahedron 1996, 52, 12745-12760.
(c) Fleming, F. F.; Lee, F.; Altundas, R.; Yung, T. J. Org. Chem. 2001, 66,
6502-6504. (d) Tohma, H.; Maegawa, T.; Kita, Y. ArkiVoc 2003, 62-70.
6780 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of Polyfunctionalized Benzo[a]quinolizinones
1
SCHEME 5a
70%): mp (Et2O) 149-150 °C; IR (KBr) 1645 cm-1; H NMR
(CDCl3) 2.34-2.49 (m, 2H), 2.56-2.72 (m, 3H), 2.80-3.04 (m,
3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.29 (d, J ) 3.6 Hz, 1H), 4.71-
4.75 (m, 1H), 4.75-4.79 (m, 1H), 6.63 (s, 1H), 6.79 (s, 1H), 7.23-
7.44 (m, 10H); 13C NMR (CDCl3) 28.1, 31.1, 34.9, 36.7, 40.9, 54.7,
55.9, 56.1, 65.3, 107.6, 111.8, 127.7, 128.0, 129.1, 129.9, 133.2,
132.6, 133.4, 134.3, 147.5, 147.9, 169.0; MS (EI) m/z (rel intensity)
492 (M+ + 1, 3), 491 (M+, 10), 382 (51), 353 (20), 272 (60), 258
(100), 244 (17), 230 (10), 205 (11), 192 (19). HRMS calcd for
C28H29NO3S2: 491.1589. Found: 491.1607
(2SR,11bRS)-2-[1,3-Dithian-2-yl]-9,10-dimethoxy-1,2,3,6,7,-
11b-hexahydrobenzo[a]quinolizin-4-one (5b). According to the
general procedure, 3a (124 mg, 0.47 mmol) was treated with
2-lithio-1,3-dithiane, prepared from 1,3-dithiane (115 mg, 0.95
mmol) and n-BuLi (0.80 mL of a 1.2 M solution in hexanes, 0.95
mmol), for 5 h. Flash column chromatography (silica gel, AcOEt)
afforded 5b as a white solid (152 mg, 85%): mp (Et2O) 158-159
1
°C; IR (KBr) 1645 cm-1; H NMR (CDCl3) 1.85-1.91 (m, 1H),
2.10-2.40 (m, 5H), 2.59-2.80 (m, 2H), 2.85-3.05 (m, 6H), 3.85
(s, 3H), 3.88 (s, 3H), 4.04 (d, J ) 7.5 Hz, 1H), 4.73-4.79 (m,
2H), 6.61 (s, 1H), 6.71 (s, 1H); 13C NMR (CDCl3) 25.6, 27.9, 29.9,
31.1, 34.0, 35.9, 40.7, 50.9, 54.1, 55.7, 55.8, 107.1, 111.6, 127.4,
a Reagents: (a) NaBH4, EtOH/H2O, 0 °C, 1 h. (b) MeSO2Cl, NEt3,
CH2Cl2, 0 °C f rt, 12 h. (c) 19, t-BuLi, -78 °C, 15 min, then 18, rt. (d)
TFA, CH2Cl2, rt.
128.2, 147.3, 147.7, 168.2; MS (EI) m/z (rel intensity) 380 (M+
+
1, 15), 379 (M+, 58), 304 (60), 273 (36), 258 (100), 245 (32), 205
(27), 192 (17), 176 (9). HRMS calcd for C19H25NO3S2: 379.1276.
Found: 379.1271. Anal. Calcd for C19H25NO3S2: C, 60.13; H, 6.64;
N, 3.69. Found: C, 59.95; H, 6.82; N, 3.86.
corresponding alcohol 17 in good yield (Scheme 5). This alcohol
was mesylated and submitted to nucleophilic displacement with
the anion obtained by deprotonation of the isoquinoline 19,
obtaining 20 as a 1:1 mixture of diastereomers. Hydrolysis of
the Boc group produced the epimeric emetine analogues 21.
In conclusion, conjugate addition reactions of sulfur-stabilized
nucleophiles to the δ-lactam unit of tetrahydrobenzo[a]benzo-
quinolizines allowed the stereocontrolled formation of carbon-
carbon bonds at the C-2 position. The attack of the nucleophile
occurred parallel to the hydrogen on C-11b. However, the
introduction of a methyl group at the C-11b position caused
the reversal of the stereochemical course of the addition. Thus,
2,11b-cis or 2,11b-trans diastereomers could be selectively
obtained. The conjugate addition-alkylation tandem reaction
also took place in good yields and with high diastereoselectivity.
Besides, the polyfunctionalized hexahydrobenzo[a]quinolizinone
systems obtained could be further elaborated toward emetine-
like structures.
(2RS,11bRS)-2-[Bis(thiophenyl)methyl]-9,10-dimethoxy-11b-
methyl-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (6a) and
(2SR,11bRS)-2-[Bis(thiophenyl)methyl]-9,10-dimethoxy-11b-
methyl-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (7a).
According to the general procedure, 3b (121 mg, 0.44 mmol) was
treated with lithio-bis(thiophenyl)methane, prepared from bis-
(thiophenyl)methane (210 mg, 0.88 mmol) and n-BuLi (0.73 mL
of a 1.2 M solution in hexanes, 0.88 mmol), for 16 h. Flash column
chromatography (silica gel, AcOEt) afforded a diastereomeric
mixture of 6a and 7a in a 80:20 diastereomeric ratio (210 mg, 93%).
Both diastereomers were separated by chromatography and char-
acterized separately. Major trans diastereomer 6a, white solid (155
mg, 74%): mp (Et2O) 130-131 °C; IR (KBr) 1635 cm-1; 1H NMR
(CDCl3) 1.72 (s, 3H), 2.02-2.05 (m, 1H), 2.06-2.11 (m, 1H),
2.46-2.55 (m, 1H), 2.58-2.64 (m, 1H), 2.79 (dd, J ) 16.4, 12.0
Hz, 1H), 2.99-3.16 (m, 1H), 3.00 (dd, J ) 12.3, 6.7 Hz, 1H),
3.31 (td, J ) 12.7, 4.7 Hz, 1H), 3.92 (s, 3H), 3.97 (s, 3H), 4.24 (d,
J ) 3.6 Hz, 1H), 4.83 (dd, J ) 13.0, 6.0 Hz, 1H), 6.60 (s, 1H),
6.90 (s, 1H), 7.19-7.44 (m, 10H); 13C NMR (CDCl3) 27.8, 32.8,
34.8, 36.3, 38.0, 38.3, 55.8, 56.1, 59.5, 65.4, 107.1, 112.1, 127.3,
127.9, 128.2, 128.9, 132.5, 132.8, 133.4, 134.3, 147.3, 147.9, 169.5;
MS (EI) m/z (rel intensity) 506 (M+ + 1, 2), 505 (M+, 6), 396
(100), 380 (9), 271 (5), 258 (17), 206 (21), 191 (5), 110 (5). HRMS
calcd for C29H31NO3S2: 505.1745. Found: 505.1729. Anal. Calcd
for C29H31NO3S2: C, 68.88; H, 6.18; N, 2.77. Found: C, 68.59;
H, 6.15; N, 2.53. Minor cis diastereomer 7a, colorless oil (50 mg,
18%): IR (KBr) 1640 cm-1; 1H NMR (CDCl3) 1.48 (s, 3H), 1.62-
1.81 (m, 1H), 2.55-2.67 (m, 5H), 2.83-2.90 (m, 2H), 3.85 (s,
3H), 3.89 (s, 3H), 4.35 (d, J ) 3.6 Hz, 1H), 4.85-4.89 (m, 1H),
6.57 (s, 1H), 6.60 (s, 1H), 7.28-7.48 (m, 10H); 13C NMR (CDCl3)
27.9, 28.6, 33.7, 35.7, 35.8, 39.8, 55.7, 56.2, 58.4, 64.7, 108.4,
111.3, 125.8, 127.9, 128.1, 129.0, 132.5, 133.0, 134.2, 134.3, 147.6,
167.8; MS (EI) m/z (rel intensity) 505 (M+, 1), 396 (100), 380 (5),
258 (39), 206 (16), 165 (11), 110 (23). HRMS calcd for C29H31-
NO3S2: 505.1745. Found: 505.1760.
Experimental Section
Conjugate Addition Reactions of Lithiodithioacetals to Benzo-
[a]quinolozidones 3a,b. General Procedure. To a solution of bis-
(thiophenyl)methane or 1,3-dithiane (2 mmol) in dry THF (10 mL)
was added n-BuLi (2 mmol) at -78 °C. The resulting mixture was
stirred at this temperature for 1 h and allowed to warm to room
temperature. A solution of benzoquinolizidone 3a or 3b (1 mmol)
in THF (10 mL) was added, and the resulting solution was stirred
for 5 or 16 h. The reaction was quenched by the addition of
saturated NH4Cl (15 mL). The organic layer was separated, and
the aqueous phase was extracted with Et2O (3 × 10 mL). The
combined organic extracts were washed with brine (2 × 10 mL),
dried (Na2SO4), and concentrated in vacuo to afford benzoquino-
lizidones 4 and/or 5, which were purified by flash column
chromatography.
(2SR,11bRS)-2-[Bis(thiophenyl)methyl]-9,10-dimethoxy-
1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (5a). According
to the general procedure, 3a (95 mg, 0.37 mmol) was treated with
lithio-bis(thiophenyl)methane, prepared from bis(thiophenyl)-
methane (170 mg, 0.73 mmol) and n-BuLi (0.60 mL of a 1.2 M
solution in hexanes, 0.73 mmol), for 5 h. Flash column chroma-
tography (silica gel, AcOEt) afforded 5a as a white solid (130 mg,
(2RS,11bRS)-2-(1,3-Dithian-2-yl)-9,10-dimethoxy-11b-methyl-
1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (6b) and (2SR,-
11bRS)-2-(1,3-Dithian-2-yl)-9,10-dimethoxy-11b-methyl-1,2,3,6,7,-
11b-hexahydrobenzo[a]quinolizin-4-one (7b). According to the
general procedure, 3b (396 mg, 1.45 mmol) was treated with
2-lithio-1,3-dithiane, prepared from 1,3-dithiane (350 mg, 2.9 mmol)
and n-BuLi (2.23 mL of a 1.3 M solution in hexanes, 2.9 mmol),
J. Org. Chem, Vol. 71, No. 18, 2006 6781

Garc´ıa et al.
for 5 h. Flash column chromatography (silica gel, AcOEt) afforded
a diastereomeric mixture of 6b and 7b in a 88:12 diastereomeric
ratio (430 mg, 75%). Both diastereomers were separated by
chromatography and characterized separately. Major trans diaste-
reomer 6b, white solid (378 mg, 66%): mp (Et2O) 184-185 °C;
afforded a diastereomeric mixture of 10a and 10a′ in a 4:1
diastereomeric ratio that could not be separated (500 mg, 65%):
1
mp (Et2O) 149-150 °C; IR (KBr) 1625 cm-1; H NMR (CDCl3)
0.55 (t, J ) 7.4 Hz, 3H major diast.), 1.03 (t, J ) 7.4 Hz, 3H
minor diast.), 1.46-1.57 (m, 1H minor diast. + 1H both diast.),
1.71-1.81 (m, 1H major diast. + 1H both diast.), 2.05-2.10 (m,
1H minor diast.), 2.15-2.26 (m, 1H both diast.), 2.30-2.93 (m,
2H major diast. + 3H both diast.), 3.63-3.72 (m, 1H minor diast.),
3.87 (s, 3H both diast.), 3.91 (s, 3H both diast.), 4.16 (d, J ) 5.9
Hz, 1H minor diast.), 4.43 (d, J ) 4.8 Hz, 1H major diast.), 4.73-
4.79 (m, 2H both diast.), 6.59 (s, 1H minor diast.), 6.62 (s, 1H
major diast.), 6.83 (s, 1H both diast.), 6.97-7.5 (m, 10H both diast.);
13C NMR (CDCl3) 10.0 (major diast.), 11.9 (minor diast.), 21.7
(major diast.), 22.8 (minor diast.), 28.3 (major diast.), 28.7 (minor
diast.), 29.6 (major diast.), 34.8 (minor diast.), 37.0 (major diast.),
37.2 (major diast.), 38.6 (minor diast.), 40.7 (major diast.), 44.6
(major diast.), 45.7 (minor diast.), 53.7 (major diast.), 55.7 (minor
diast.), 55.9, 56.0 (both diast.), 58.9 (major diast.), 64.4 (minor
diast.), 107.8 (major diast.), 108.6 (minor diast.), 110.8 (major
diast.), 111.6 (minor diast.), 125.9, 126.1, 127.9, 127.9, 128.2, 128.3,
128.6, 128.8, 128.9, 129.8, 132.5, 133.5, 133.6, 135.1 (both diast.),
147.4 (major diast.), 147.7 (major diast.), 147.8 (minor diast.), 148.2
(minor diast.), 170.9 (major diast.), 171.2 (minor diast.); MS (EI)
m/z (rel intensity) 520 (M+ + 1, 7), 519 (M+, 15), 410 (52), 381
(24), 300 (62), 286 (100), 272 (34), 230 (16), 205 (16), 192 (11),
135 (7), 109 (8), 91 (4).
1
IR (KBr) 1640 cm-1; H NMR (CDCl3) 1.60 (s, 3H), 1.76-1.96
(m, 3H), 2.06-2.13 (m, 1H), 2.38-2.45 (m, 2H), 2.49-0.67 (m,
1H), 2.75-2.89 (m, 4H), 2.96-3.10 (m, 2H), 3.27 (td, J ) 12.5,
4.8 Hz, 1H), 3.84 (s, 3H), 3.88 (s, 3H), 3.95 (d, J ) 6.2 Hz, 1H),
4.77 (dd, J ) 13.1, 6.3 Hz, 1H), 6.55 (s, 1H), 6.72 (s, 1H); 13C
NMR (CDCl3) 25.8, 27.5, 29.6, 32.5, 33.7, 35.6, 37.4, 39.3, 51.4,
55.6, 55.8, 59.1, 106.3, 111.9, 126.8, 132.6, 147.1, 147.6, 169.1;
MS (EI) m/z (rel intensity) 394 (M+ + 1, 4), 393 (M+, 15), 378
(100), 271 (8), 242 (6), 206 (5). HRMS calcd for C20H27NO3S2:
393.1432. Found: 393.1432. Anal. Calcd for C20H27NO3S2: C,
61.04; H, 6.91; N, 3.56. Found: C, 60.64; H, 6.90; N, 3.51. Minor
cis diastereomer 7b, colorless oil (52 mg, 9%): IR (KBr) 1625
1
cm-1; H NMR (CDCl3) 1.60 (s, 3H), 1.61-1.79 (m, 1H), 1.82-
1.97 (m, 1H), 2.09-2.18 (m, 1H), 2.33-2.56 (m, 2H), 2.58 (d, J
) 11.9 Hz, 1H), 2.55-2.64 (m, 1H), 2.84-2.87 (m, 1H), 2.88-
3.00 (m, 6H), 3.85 (s, 3H), 3.88 (s, 3H), 4.03 (d, J ) 5.5 Hz, 1H),
4.85-4.93 (m, 1H), 6.56 (s, 1H), 6.62 (s, 1H); 13C NMR (CDCl3)
25.9, 28.0, 28.8, 30.4, 33.8, 35.8, 41.1, 52.5, 55.8, 56.3, 58.4, 108.5,
111.4, 125.9, 134.4, 147.7, 167.8; MS (EI) m/z (rel intensity) 394
(M + 1, 16), 393 (M+, 9), 378 (100), 271 (11), 258 (13), 242 (15),
206 (10), 119 (24), 91 (7). HRMS calcd for C20H27NO3S2:
393.1432. Found: 393.1437.
(2SR,3RS,11bRS)-2-[1,3-Dithian-2-yl]-3-ethyl-9,10-dimethoxy-
1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (10b). Accord-
ing to the general procedure, 3a (259 mg, 0.99 mmol) was treated
with 2-lithio-1,3-dithiane, prepared from 1,3-dithiane (240 mg, 1.98
mmol) and n-BuLi (1.98 mL of a 1.0 M solution in hexanes, 1.98
mmol), for 5 h, and EtI (0.15 mL, 1.98 mmol). Flash column
chromatography (silica gel, AcOEt) afforded 10b as a single
diastereomer (322 mg, 80%): mp (Et2O) 167-168 °C; IR (KBr)
1645 cm-1; 1H NMR (CDCl3) 0.84 (t, J ) 7.3 Hz, 3H), 1.47-1.59
(m, 1H), 1.75-1.97 (m, 2H), 2.00-2.03 (m, 1H), 2.04-2.09 (m,
2H), 2.48-2.69 (m, 2H), 2.71-2.76 (m, 2H), 2.77-288 (m, 5H),
3.76 (s, 3H), 3.79 (s, 3H), 4.09 (d, J ) 8.3 Hz, 1H), 4.62-4.69
(m, 1H), 4.70-4.79 (m, 1H), 6.52 (s, 1H), 6.61 (s, 1H); 13C NMR
(CDCl3) 11.4, 24.0, 25.7, 28.2, 28.7, 29.9, 36.7, 39.8, 44.5, 49.9,
52.6, 55.5, 55.8, 107.5, 111.2, 126.9, 128.8, 147.3, 147.4, 170.5;
MS (EI) m/z (rel intensity) 408 (M+ + 1, 12), 407 (M+, 43), 378
(10), 332 (39), 301 (13), 286 (100), 270 (20), 258 (25), 230 (10),
205 (43), 192 (10), 119 (37). HRMS calcd for C21H29NO3S2:
407.1589. Found: 407.1589.
(2SR,3RS,11bRS)-9,10-Dimethoxy-2,3-phenylthiomethano-
1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (8). According
to the general procedure, 3a (115 mg, 0.45 mmol) was treated with
lithio-bis(thiophenyl)methane, prepared from bis(thiophenyl)-
methane (213 mg, 0.89 mmol) and n-BuLi (0.60 mL of a 1.5 M
solution in hexanes, 0.89 mmol), for 16 h. Flash column chroma-
tography (silica gel, AcOEt) afforded 5a (11 mg, 5%) and the
cyclopropane derivative 8 as a white solid (120 mg, 68%): mp
(Et2O) 169-170 °C; IR (KBr) 1634 cm-1; 1H NMR (CDCl3) 1.81-
1.98 (m, 1H), 1.98-2.05 (m, 1H), 2.20 (dd, J ) 8.3, 3.6 Hz, 1H),
2.57-2.67 (m, 1H), 2.68-2.72 (m, 1H), 2.74-2.79 (m, 2H), 299
(t, J ) 3.6 Hz, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.45 (dd, J ) 11.9,
4.4 Hz, 1H), 4.85-4.91 (m, 1H), 6.59 (s, 1H), 6.60 (s, 1H), 7.17-
7.41 (m, 5H); 13C NMR (CDCl3) 20.5, 22.5, 27.9, 28.4, 30.4, 38.7,
51.6, 55.7, 55.9, 108.3, 111.4, 125.8, 127.0, 127.3, 128.9, 136.3,
147.6, 147.7, 167.6; MS (EI) m/z (rel intensity) 382 (M+ + 1, 10),
381 (M+, 37), 272 (100), 258 (25), 245 (56), 230 (14), 206 (80),
192 (58), 176 (34), 147 (10), 91 (11), 77 (12). HRMS calcd for
C22H23NO3S: 381.1399. Found: 381.1404.
Tandem Conjugate Addition Reactions of Lithio Dithio-
acetals-EtI Trap. General Procedure. To a solution of bis-
(thiophenyl)methane or 1,3-dithiane (2 mmol) in dry THF (10 mL)
was added n-BuLi (2 mmol) at -78 °C. The resulting mixture was
stirred at this temperature for 1 h and allowed to warm to room
temperature. A solution of 3a or 3b (1 mmol) in THF (10 mL)
was added, and the resulting solution was stirred for 5 or 16 h. EtI
(2 mmol) was added, and the reaction mixture was further stirred
for 6 h. The reaction was quenched by the addition of saturated
NH4Cl (15 mL). The organic layer was separated, and the aqueous
phase was extracted with Et2O (3 × 10 mL). The combined organic
extracts were washed with brine (2 × 10 mL), dried (Na2SO4),
and concentrated in vacuo to afford benzoquinolizidones 9-12,
which were purified by flash column chromatography.
(2RS,3SR,11bRS)-2-[Bis(thiophenyl)methyl]-3-ethyl-9,10-
dimethoxy-11b-methyl-1,2,3,6,7,11b-hexahydrobenzo[a]quino-
lizin-4-one (11a). According to the general procedure, 3b (295 mg,
1.08 mmol) was treated with lithio-bis(thiophenyl)methane, prepared
from bis(thiophenyl)methane (513 mg, 2.16 mmol) and n-BuLi
(2.27 mL of a 0.95 M solution in hexanes, 2.16 mmol), for 16 h,
and EtI (0.17 mL, 2.16 mmol). Flash column chromatography (silica
gel, 70% hexane/AcOEt) afforded a diastereomeric mixture of 11a
and 12a in an 85:15 ratio (385 mg, 67%). Only the major compound
11a could be separated and fully characterized: mp (Et2O) 149-
1
150 °C; IR (KBr) 1625 cm-1; H NMR (CDCl3) 0.13 (t, J ) 7.2
Hz, 3H), 1.16-1.27 (m, 1H), 1.66 (s, 3H), 1.93-1.96 (m, 1H),
1.97-2.00 (m, 1H), 2.00-2.10 (m, 1H), 2.54 (dd, J ) 16.3, 3.7
Hz, 1H), 2.77-2.84 (m, 1H), 2.85 (td, J ) 16.3, 5.7 Hz, 1H), 3.14-
3.18 (m, 1H), 3.25 (td, J ) 13.2, 4.5 Hz, 1H), 3.88 (s, 3H), 3.96
(s, 3H), 4.28 (d, J ) 1.6 Hz, 1H), 4.80 (dd, J ) 13.2, 5.7 Hz, 1H),
6.57 (s, 1H), 6.96 (s, 1H), 6.97-7.5 (m, 10H); 13C NMR (CDCl3)
8.0, 19.6, 28.7, 32.9, 35.5, 36.4, 37.1, 45.1, 55.9, 56.1, 58.9, 64.3,
107.6, 112.1, 127.4, 128.0, 128.5, 129.1, 132.6, 132.9, 133.7, 134.1,
134.4, 147.3, 147.8, 171.5; MS (EI) m/z (rel intensity) 533 (M+,
3), 518 (2), 424 (100), 314 (4), 286 (18), 206 (7), 123 (5). HRMS
calcd for C31H35NO3S2: 533.2058. Found: 533.2054
(2SR,3RS,11bRS)-2-[Bis(thiophenyl)methyl]-3-ethyl-9,10-
dimethoxy-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (10a)
and (2SR,3SR,11bRS)-2-[Bis(thiophenyl)methyl]-3-ethyl-9,10-
dimethoxy-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (10a′).
According to the general procedure, 3a (381 mg, 1.47 mmol) was
treated with lithio-bis(thiophenyl)methane, prepared from bis-
(thiophenyl)methane (684 mg, 2.9 mmol) and n-BuLi (2.45 mL of
a 1.2 M solution in hexanes, 2.9 mmol), for 5 h, and EtI (0.38 mL,
4.8 mmol). Flash column chromatography (silica gel, AcOEt)
(2RS,3SR,11bRS)-2-[1,3-Dithian-2-yl]-3-ethyl-9,10-dimethoxy-
11b-methyl-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (11b).
6782 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of Polyfunctionalized Benzo[a]quinolizinones
According to the general procedure, 3b (335 mg, 1.20 mmol) was
treated with 2-lithio-1,3-dithiane, prepared from 1,3-dithiane (295
mg, 1.60 mmol) and n-BuLi (2.45 mL of a 1.0 M solution in
hexanes, 1.98 mmol), for 5 h, and EtI (0.38 mL, 4.8 mmol). Flash
column chromatography (silica gel, AcOEt) afforded 11b as a single
diastereomer (258 mg, 50%): mp (Et2O) 176-177 °C; IR (KBr)
1645 cm-1; 1H NMR (CDCl3) 0.62 (t, J ) 7.1 Hz, 3H), 1.25-1.48
(m, 1H), 1.56 (s, 3H), 1.72-2.03 (m, 3H), 2.13-2.30 (m, 2H),
2.55 (dd, J ) 16.4, 4.5 Hz, 1H), 2.61-2.67 (m, 1H), 2.78-3.04
(m, 6H), 3.26 (td, J ) 12.7, 4.6 Hz, 1H), 3.82 (s, 3H), 3.88 (s,
3H), 4.26 (d, J ) 2.4 Hz, 1H), 4.79 (dd, J ) 13.4, 6.7 Hz, 1H),
6.53 (s, 1H), 6.73 (s, 1H); 13C NMR (CDCl3) 9.3, 19.9, 26.3, 28.3,
30.7, 31.3, 32.8, 35.7, 36.7, 37.3, 44.7, 50.9, 55.7, 55.9, 58.7, 106.5,
111.9, 126.9, 132.9, 147.3, 147.6, 171.5; MS (EI) m/z (rel intensity)
421 (M+, 11), 406 (100), 298 (11), 270 (12), 258 (25), 204 (4),
119 (12). HRMS calcd for C22H31NO3S2: 421.1745. Found:
421.1741.
Deprotection of Thioacetals. General Procedure. A solution
of the benzoquinolizidones 5a, 6a, 6b, or 10a (1 mmol) in CH3-
CN/H2O (2:1, 15 mL) was treated with TFA (10 mmol) at room
temperature. PIDA (1.3 mmol) was added in portions, and the
resulting mixture was stirred for 1.5 h. The reaction mixture was
extracted with hexane (3 × 20 mL). The combined organic extracts
were treated with saturated NaHCO3, maintaining an acidic media
(pH ≈ 6). The aqueous phase was extracted with CHCl3 (3 × 20
mL), dried (Na2SO4), and concentrated in vacuo. Flash column
chromatography (silica gel) afforded the 2-formylbenzoquinolizi-
dones 14, 15, or 16.
(2SR,11bRS)-2-Formyl-9,10-dimethoxy-1,2,3,6,7,11b-hexahy-
drobenzo[a]quinolizin-4-one (14). According to the general
procedure, benzoquinolizidone 5a (102 mg, 0.20 mmol) was treated
with TFA (0.2 mL, 2.0 mmol) and PIDA (86 mg, 0.26 mmol).
Flash column chromatography (silica gel, 20% AcOEt/NH3) af-
forded 14 as a colorless oil (48 mg, 80%): IR (KBr) 1719, 1636
cm-1; 1H NMR (CDCl3), 1.94-2.06 (m, 1H), 2.64-2.71 (m, 2H),
2.72-2.90 (m, 5H), 3.86 (s, 3H), 3.93 (s, 3H), 4.58 (dd, J ) 10.3,
4.6 Hz, 1H), 4.75-4.82 (m, 1H), 6.60 (s, 1H), 6.65 (s, 1H), 9.82
(s, 1H); 13C NMR (CDCl3) 28.2, 29.4, 31.3, 39.5, 44.0, 53.4, 55.0,
56.0, 107.9, 111.5, 127.1, 127.8, 147.8, 147.9, 167.0, 200.4; MS
(EI) m/z (rel intensity) 290 (M+ + 1, 11), 289 (M+, 50), 261 (32),
245 (95), 232 (19), 205 (35), 192 (100), 176 (33), 164 (8), 146 (9),
115 (8), 77 (10). HRMS calcd for C16H19NO4: 289.1314. Found:
289.1344.
3H both diast.), 4.55-4.63 (m, 1H both diast.), 4.77-4.83 (m, 1H
both diast.), 6.60 (s, 1H major diast.), 6.62 (s, 1H minor diast.),
6.66 (s, 1H major diast.), 6.80 (s, 1H minor diast.), 9.71 (s, 1H,
minor diast.), 9.83 (s, 1H, major diast.); 13C NMR (CDCl3) 11.9
(major diast.), 12.9 (minor diast.), 22.6 (minor diast.), 24.8 (major
diast.), 27.1 (minor diast.), 27.2 (major diast.), 28.5 (both diast.),
39.6 (minor diast.), 39.8 (major diast.), 41.1 (major diast.), 41.6
(minor diast.), 46.3 (major diast.), 47.8 (minor diast.), 53.1 (major
diast.), 54.9 (minor diast.), 55.8 (both diast.), 56.1 (both diast.),
108.0, 111.5 (both diast.), 126.9 (minor diast.), 127.1 (major diast.),
128.1 (minor diast.), 128.2 (major diast.), 147.8, 148.0 (both diast.),
170.1 (major diast.), 170.3 (minor diast.), 201.2 (minor diast.), 202.1
(major diast.); MS (EI) m/z (rel intensity) 317 (M+, 37), 289 (50),
274 (53), 258 (33), 246 (100), 218 (29), 205 (73), 191 (88), 176
(38), 146 (14), 130 (18), 115 (11), 77 (13). HRMS calcd for C18H23-
NO4: 317.1627. Found: 317.1617.
(2RS,11bRS)-2-Hydroxymethyl-9,10-dimethoxy-11b-methyl-
1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (17). NaBH4
(50 mg, 1.3 mmol) was added in portions to a solution of aldehyde
15 (100 mg, 0.33 mmol) in 2:1 EtOH/H2O (10 mL) at 0 °C, keeping
pH ) 7 by addition of saturated NH4Cl. The resulting solution was
stirred for 1 h. H2O was added (10 mL), and the mixture was
extracted with AcOEt (3 × 15 mL), dried (Na2SO4), and concen-
trated in vacuo. Flash column chromatography (silica gel, AcOEt)
afforded the 2-hydroxymethylbenzoquinolizidone 17 as a colorless
1
oil (80 mg, 80%): IR (KBr) 3384, 1609 cm-1; H NMR (CDCl3)
1.45-1.55 (m, 1H), 1.61 (s, 3H), 1.90 (broad s, 1H), 2.07 (dd, J )
17.0, 11.9 Hz, 1H), 2.26-2.63 (m, 4H), 2.77-2.94 (m, 2H), 3.46-
3.65 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.84-4.95 (m, 1H), 6.58
(s, 1H), 6.64 (s, 1H); 13C NMR (CDCl3) 28.1, 28.9, 31.2, 34.6,
35.8, 40.6, 55.8, 56.2, 58.6, 66.4, 108.4, 111.3, 125.9, 134.7, 147.6,
147.7, 168.6; MS (EI) m/z (rel intensity) 305 (M+, 5), 290 (100),
274 (6), 206 (13), 190 (6), 165 (4), 145 (3), 115 (7). HRMS. Calcd
for C17H23NO4: 305.1627. Found: 305.1617.
(2RS,11bRS)-2-Methanesulfonyloxymethyl-9,10-dimethoxy-
11b-methyl-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (18).
MeSO2Cl (0.06 mL, 0.73 mmol) and NEt3 (0.1 mL, 0.73 mmol)
were added to a solution of alcohol 17 (193 mg, 0.61 mmol) in
CH2Cl2 (10 mL) at 0 °C. The resulting solution was allowed to
warm to room temperature and stirred for 16 h. The solvent was
concentrated in vacuo. Flash column chromatography (silica gel,
AcOEt) afforded the mesylate 18 as a yellow oil (215 mg, 90%):
IR (KBr) 1621, 1255 cm-1; 1H NMR (CDCl3) 1.03-1.08 (m, 1H),
1.09-1.32 (m, 1H), 1.23 (s, 3H), 1.47-1.61 (m, 1H), 1.62 (s, 3H),
1.88 (td, J ) 8.7, 3.6 Hz, 1H), 2.12 (dd, J ) 13.9, 3.9 Hz, 1H),
2.44-2.72 (m, 3H), 2.78-2.90 (m, 2H), 3.83 (s, 3H), 3.85 (s, 3H),
4.78-4.91 (m, 1H), 6.50 (s, 1H), 6.59 (s, 1H); 13C NMR (CDCl3)
12.8, 14.0, 16.3, 28.6, 29.6, 31.3, 34.8, 36.1, 55.7, 56.1, 57.9, 108.7,
111.1, 125.4, 136.9, 147.4, 147.6, 170.9; MS (EI) m/z (rel intensity)
287 (6), 272 (100), 256 (6), 115 (2), 91 (2), 77 (2). HRMS calcd
for C18H25NO6S: 383.1403. Found: 387.1393.
(1′RS,2RS,11bRS)- and (1′SR,2RS,11bRS)-2-(6′,7′-Dimethoxy-
1′,2′,3′,4′-tetrahydroisoquinolin-1-ylmethyl)-9,10-dimethoxy-
11b-methyl-1,2,3,6,7,11b-hexahydrobenzo[a]quinolizin-4-one (21).
t-BuLi (0.8 mL of a 1.1 M solution, 0.88 mmol) was added to a
solution of isoquinoline 1928 (260 mg, 0.88 mmol) in THF (7 mL)
at -78 °C. After 15 min, a solution of mesylate 13 (85 mg, 0.22
mmol) in THF (2 mL) was added, and the resulting solution was
stirred for 5 min. The reaction mixture was allowed to warm to 0
°C and stirred at this temperature for 3 h. H2O was added (10 mL),
and the mixture was extracted with Et2O (3 × 15 mL). The
combined organic extracts were washed with brine (3 × 10 mL),
dried (Na2SO4), and concentrated in vacuo to afford 20, which was
deprotected without further purification. Thus, crude 20 was treated
(2RS,11bRS)-2-Formyl-9,10-dimethoxy-11b-methyl-1,2,3,6,7,-
11b-hexahydrobenzo[a]quinolizin-4-one (15). According to the
general procedure, benzoquinolizidone 6a (166 mg, 0.33 mmol)
was treated with TFA (0.3 mL, 3.3 mmol) and PIDA (138 mg,
0.43 mmol). Flash column chromatography (silica gel, 20% AcOEt/
NH3) afforded 15 as a white solid (80 mg, 80%): IR (KBr) 1675,
1
1615 cm-1; H NMR (CDCl3) 1.52-1.68 (m, 1H), 1.61 (s, 3H),
2.41-2.50 (m, 1H), 2.53-2.84 (m, 5H), 2.90-2.97 (m, 1H), 3.80
(s, 3H), 3.83 (s, 3H), 4.81-4.89 (m, 1H), 6.53 (s, 1H), 6.60 (s,
1H), 9.66 (s, 1H); 13C NMR (CDCl3) 27.6, 28.7, 30.6, 35.8, 36.9,
41.5, 55.7, 56.0, 58.2, 108.0, 111.3, 125.9, 133.4, 147.7, 166.5,
200.6; MS (EI) m/z (rel intensity) 304 (M+ + 1, 3), 303 (M+, 10),
288 (100), 272 (2), 260 (6), 246 (3), 206 (4), 190 (3). HRMS calcd
for C17H21NO4: 303.1470. Found: 303.1476.
(2SR,3RS,11bRS)-3-Ethyl-2-formyl-9,10-dimethoxy-1,2,3,6,7,-
11b-hexahydrobenzo[a]quinolizin-4-one (16). According to the
general procedure, benzoquinolizidone 10a (274 mg, 0.52 mmol,
4:1 epimeric mixture in C-3) was treated with TFA (0.5 mL, 5.2
mmol) and PIDA (220 mg, 0.69 mmol). Flash column chromatog-
raphy (silica gel, 20% AcOEt/NH3) afforded 16 as a colorless oil,
as a 4:1 epimeric mixture in C-3. Data of the mixture are given
1
(117 mg, 70%): IR (KBr) 1720, 1633 cm-1; H NMR (CDCl3)
0.89-1.03 (m, 3H both diast.), 1.40-1.50 (m, 1H minor diast.),
1.50-2.03 (m, 3H both diast. + 1H major diast.), 2.58-2.91 (m,
3H both diast. + 1H major diast.), 2.41-2.50 (m, 1H both diast.),
2.97-3.03 (m, 1H minor diast.), 3.85 (s, 3H both diast.), 3.88 (s,
(28) Boc-protected isoquinoline 19 was prepared by treatment of
commercially available 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with
di-tert-butyl dicarbonate. See: Coppola, G. M. J. Heterocycl. Chem. 1991,
28, 1769-1772.
J. Org. Chem, Vol. 71, No. 18, 2006 6783

Garc´ıa et al.
with TFA (0.23 mL, 3 mmol) in CH2Cl2 (10 mL) at room
temperature for 1 h. Saturated NaHCO3 (10 mL) was added, and
the organic phase was washed with brine (3 × 10 mL), dried (Na2-
SO4), and concentrated in vacuo. Flash column chromatography
(silica gel, AcOEt) afforded 21 as 1:1 mixture of C-1′ epimers (50
mg, 45% overall two steps): IR (KBr) 3314, 1639 cm-1; 1H NMR
(CDCl3) 1.97 (broad s, 1H both diast.), 2.50-3.05 (m, 8H both
diast.), 3.26 (s, 3H one diast.), 3.21-3.48 (m, 3H, both diast.), 3.67
(s, 3H, other diast.), 3.80 (s, 6H, both diast.), 3.84 (s, 18H both
diast.), 3.70-3.85 (m, 1H both diast.), 4.36-4.41 (m, 1H both
diast.), 4.58-5.05 (m, 3H both diast.), 6.21 (s, 1H one diast.), 6.45
(s, 1H other diast.), 6.55-6.61 (m, 3H both diast.); 13C NMR
(CDCl3) 25.6 (both diast.), 27.8 (one diast.), 28.4 (other diast.),
28.6 (both diast.), 40.6, 42.4, 42.6, 43.5, 44.6, 54.9, 55.8, 55.9 (one
and/or other diast.), 58.5 (one diast.), 60.9 (other diast.), 108.1,
108.9, 109.3, 109.8, 111.7, 112.7, 124.4, 124.9, 125.8, 126.6, 126.9,
127.1, 147.4, 147.6, 147.7, 147.8, 147.9, 148.1 (one and/or other
diast.), 171.1 (one diast.), 171.7 (other diast.); MS (EI) m/z (rel
intensity) 234 (1), 221 (1), 192 (100), 176 (6), 164 (1), 148 (3),
131 (2), 105 (1), 91 (1).
Acknowledgment. Financial support from MCYT (BQU2003-
03239), Gobierno Vasco, and Universidad del Pa´ıs Vasco is
gratefully acknowledged. We also thank Gobierno Vasco for a
grant (E.G.).
Supporting Information Available: Experimental procedures
1
and full characterization data for compounds 1-3. Copies of H
and 13C NMR spectra of compounds described and selected 2D
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060903W
6784 J. Org. Chem., Vol. 71, No. 18, 2006