A formal total synthesis of the marine alkaloid aaptamine

Article abstract of DOI:10.1016/j.tet.2008.03.036

A new strategy for the synthesis of benzo[de][1,6]naphthyridine derivative 2,3,3a,4,5,6-hexahydroaaptamine, which involves the construction of the isoquinoline ring after elaboration of the quinoline moiety, is described. Since 2,3,3a,4,5,6-hexahydroaaptamine has been previously synthesized as a key intermediate en route to the marine alkaloid aaptamine, access to this compound represents a formal total synthesis of the natural product.

Full text of DOI:10.1016/j.tet.2008.03.036

Tetrahedron 64 (2008) 5236–5245
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A formal total synthesis of the marine alkaloid aaptamine
,
Enrique L. Larghi a, Blaise V. Obrist b, Teodoro S. Kaufman a
*
a Instituto de Qu´ımica Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioqu´ımicas y Farmace´uticas, Universidad Nacional de Rosario,
Suipacha 531, S2002LRK Rosario, Argentina
b Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy for the synthesis of benzo[de][1,6]naphthyridine derivative 2,3,3a,4,5,6-hexahydroaapt-
Received 6 February 2008
Received in revised form 10 March 2008
Accepted 12 March 2008
amine, which involves the construction of the isoquinoline ring after elaboration of the quinoline moiety,
is described. Since 2,3,3a,4,5,6-hexahydroaaptamine has been previously synthesized as
a key
intermediate en route to the marine alkaloid aaptamine, access to this compound represents a formal
total synthesis of the natural product.
Available online 15 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Formal total synthesis
Aaptamine
Benzo[de][1,6]naphthyridine alkaloids
2,3,3a,4,5,6-Hexahydroaaptamine
1. Introduction
Singapore4i and aaptamine itself was reported from Luffariella sp.
(Dictyoceratida),4m while modified aaptamines 9–12 have been
The aaptamines1 are marine alkaloids, which contain a benzo-
[de][1,6]naphthyridine framework;2 this nucleus was studied the-
oretically by the group of Efros3 a few years before being first found
in nature by Nakamura and co-workers, in 1982.1 To date, seven
naturally occurring tricyclic members of this family are known
(Fig. 1), and all of them have been isolated from marine sponges
belonging to the genera Aaptos4a (Hadromerida, Suberitidae) and
Suberites (Aplysinellidae, Verongida).4b
The aaptamine family includes aaptamine (1), first isolated from
an Okinawan specimen of Aaptos aaptos1,4a,c and recently observed
in other Aaptos sponges,4d,e 9-demethylaaptamine (2),4c,f bisde-
methylaaptamine (3),4g its 9-O-sulfate (4),4g isoaaptamine (5),4d,h–j
9-demethyloxyaaptamine (6),4c,h,k and 4-N-methylaaptamine (7).4l
Characterization of compound 8 has also been reported, but this
ketal is assumed to be an isolation artifact.4c,i These sponges also
produce alkaloids carrying rearranged 5,8-diazabenzo[cd]azulene
skeletons.2a
isolated from Xestospongia sp. (Haplosclerida, sub-class Ceractino-
morpha)6a,b and other sponges,6c including Aaptos suberitoides
(Hadromerida, Tethyidae),6d,e this hypothesis is no longer assumed
as valid.
Interestingly, the 1H-benzo[de][1,6]naphthyridine framework is
embedded in other structurally or biologically interesting natural
products of marine origin. Examples of this are a pyridoacridine
alkaloid isolated from the Indonesian sponge Biemna fortis, which
proved to cause neurite outgrowth on the murine neuroblastoma
cell line Neuro 2A,2b and a series of complex cytotoxic compounds,
which have been recently reported from crimson Suberea sponges
(Aplysinellidae, Verongida) native to the Coral Sea.2c
However, the occurrence of this heterocyclic skeleton is not
restricted to natural products from marine sponges, as the neca-
torones, which are fungal alkaloids, also display the related 1H-
benzo[de,h][1,6]naphthyridine backbone.2d,e In addition, tricyclic
azakynurenic acids carrying a functionalized 1H-benzo[de][1,6]-
naphthyridine system have been recently synthesized as analogs
of the quinolone-type kynurenic acids and NMDA-glycine
antagonists.2f
The aaptamines display many interesting biological activities.
Due to their antagonistic effects on b-adrenergic receptors, a car-
diac activity has been described for 1,4c,7 suggesting that it could be
a competitive antagonist of b-adrenoreceptors in vascular smooth
muscles.
The aaptamines were once considered as taxonomic markers for
the Hadromerida order within the sub-class of Tetractinomorpha
and also of the Suberitidae family of sponges.5 However, since
Brazilian specimens of Aaptos were found to be devoid of aapt-
amines,5c and due to the facts that isoaaptamine was isolated
from a Hymeniacidon sp. (Halichondrida) sponge in the coasts of
Aaptamine and related natural products have also important
* Corresponding author. Tel./fax: þ54 341 4370477.
E-mail address: kaufman@iquios.gov.ar (T.S. Kaufman).
antineoplastic effects4h,j,8a–c on different tumor cell lines such as
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.036

E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
5237
6
7
6a
8
R1O
R2O
MeO
R
MeO
MeO
MeO
5
4
A
B
9
N
N
N
N
9b
C
Me
N
9a
3a
3
N
N
N
N
R3
R1
1
2
R2
1 R1=R2= Me, R3= H
6 R= O
8 R= (OMe)2
7
9 R1= Et, R2= Me
10 R1= OH, R2= H
2 R1= Me, R2= H, R3= H
3 R1= R2= H, R3= H
4 R1= H, R2= SO2H, R3= H
5 R1=R3= Me, R2= H
MeO
O
MeO
MeO
O
P
N
N
N
O
MeO
Bn
Bn
-O
N
N
N+
14
Cl-
N
Me
R
11 R= H
12 R= CHMe2
13
Figure 1. Chemical structures of the aaptamines 1–7, ketal 8, modified aaptamines 9–12, and two of their semisynthetic derivatives (13 and 14).
murine leukemia P388 (1 and 5), KB16 cells (1, 5, and 6),8d Ehrlich
tumor cells (2 and 4),4b,8d HeLa,4j A549, and HT29 transfected hu-
man osteosarcoma MG63 cells (1).6d,9 However, it has been repor-
ted that 6 and 7 are not toxic to Vero cells at a concentration of
20 mg/mL.4l Recently, aaptamine was launched in the chemical–
pharmaceutical market as a potent anti-tumor agent by A.G. Sci-
entific, Inc. and other companies.8d
In addition, aaptamine and its congeners have demonstrated to
display several other pharmacological activities, including antimi-
crobial effects4i toward Gram-(þ) bacteria exemplified by Staphy-
lococcus aureus as well as against Gram-(ꢀ) microorganisms, such
as Escherichia coli and Vibrio anguillarum bacterial strains, and to
have anti-fungal properties, tested against the yeast Candida
tropicalis.6a
CO2H
H
HO
HO
HO
O
HO
HO
[O]
[O]
B
A
N
N
-CO2
N
C
N
H2N
N
Pictet-
H
Spengler
17
3
3a
cyclization
CO2H
NH2
HO
1 and congeners
HO
OHC
NH2
16
15
Scheme 1. Proposed biosynthetic pathway for aaptamine.14b
So far, a handful of other synthetic approaches to these unique
alkaloids have been published.15a Isoaaptamine (5),4f,12d demethyl-
(oxy)aaptamine (6),15b and other derivatives have also been syn-
thesized, an unsuccessful attempt of synthesizing aaptamine has
been informed,15c and the conversion of 1 into isoaaptamine 5 and
other aaptamine derivatives has been disclosed by the group of
Pettit.4f Therefore, a synthesis of aaptamine constitutes an indirect
entry to some of its most important related natural products.
The published syntheses of aaptamine use either the isoquino-
line (AB) or quinoline (AC) components of the benzo[de][1,6]-
naphthyridine ring as the nucleus onto which the third ring is
constructed. Syntheses starting from isoquinoline derivatives
(AB/C) include the routes developed by Cava,16a Yamanaka,16b
Tollari,16c Molina,16d–f and Joule.16g,h On the other hand, the syn-
theses by Kelly,16i Raphael,16j and Sato16k proceed through quino-
line-type intermediates (AC/B).
Compounds 1 and 5 also behave as potent inhibitors of protein
kinase C (PKC) in a cell adherence assay, as claimed in a patent;10a,b
aaptamine is also
a glutamine-fructose-6-phosphate amido-
transferase (GFAT)4d,g and monoaminooxidase A (MAO A)10c in-
hibitor, and these heterocycles also demonstrated to behave as
sortase inhibitors.10d The natural product 1 has also shown to have
in vitro antioxidant effects11a and antidepressant-like activity in the
forced swim test.11b
Some antiviral activities of the naturally occurring aaptamines
have been recently reported. These include anti-HIV-1 properties
for 1, 5, and 6,1,4c,12a and the ability to act as an agent impairing
herpes simplex virus type 1 skin penetration, for 7.12b Also, syn-
thetic and semisynthetic derivatives of isoaaptamine demonstrated
to possess interesting antileishmania, antineoplastic, and antima-
larial properties, as well as activity against Mycobacterium intra-
cellulare.12c,d In addition, isoaaptamine (5) and aaptamine (1) have
been chemically converted by the group of Pettit into the cytotoxic
prodrug Hystatin 1 (13) and the cancer cell growth inhibitor Hys-
tatin 2 (14), respectively.13
Interestingly, the syntheses employing quinolin-4-one de-
rivatives as key intermediates suffer from different drawbacks,
including the use of uncommon reagents or special reaction con-
ditions, low yielding steps, or the production of unwanted side
products.16i–k
Here, we wish to report the synthesis of 2,3,3a,4,5,6-hexahy-
droaaptamine (18), through an AC/B approach. Taking into ac-
count that 18 was the penultimate intermediate of Pelletier and
Cava’s synthesis of aaptamine,16a this constitutes a formal total
synthesis of aaptamine. Noteworthy, the published access to 18
employed an isoquinoline derivative as starting material, thus
involving an AB/C sequence.
From the biosynthetic point of view, the aaptamine skeleton has
been assumed to be derived from the biochemical Pictet–Spengler
condensation of L-DOPA (15) with a biosynthetic equivalent of b-
alanine aldehyde (16)14a to form the (tetrahydro)isoquinoline
skeleton (17) followed by oxidative closure to form the piperidine
ring C, as depicted in Scheme 1.
Subsequent decarboxylation and dehydrogenation would then
afford bisdemethylaaptamine (3), from which 1 and its congeners
could be formed by means of biochemical methylation and oxida-
tion reactions. Interestingly, a biomimetic approach yielding com-
pound 3 and the related bisdemethyl(oxy)aaptamine (3a), not yet
isolated, has been recently published.14b
2. Results and discussion
Our synthetic plan toward 18 was based on the retrosynthetic
analysis shown in Scheme 2, which entails the successive formation

5238
E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
Jackson's isoquinoline synthesis
Friedel Crafts acylation
Johnson´s
quinolin-4-one
synthesis
MeO
MeO
MeO
MeO
MeO
MeO
B
A
A
N
N
O
H
C
C
N
NH2
19
Reductive amination
H
PG
Aza-Michael addition
18
20
Scheme 2. Retrosynthetic analysis of 2,3,3a,4,5,6-hexahydroaaptamine (18).
of rings C and B from the known aniline derivative 19,17 through the
intermediacy of protected quinolin-4-one derivative 20; in turn,
this could be formed by a Johnson (Elderfield–Johnson) synthetic
sequence,18 entailing an aza-Michael addition of 19 to an acrylate
ester, followed by a Friedel–Crafts-type acylation.
The synthesis commenced with the preparation of aniline 19,
which was achieved in 87% yield through the Curtius–Yamada
rearrangement19 of commercially available 2,3-dimethoxybenzoic
acid (21) with diphenylphosphoryl azide in refluxing EtOH,
followed by basic hydrolysis of the intermediate ethyl carbamate 22
(Scheme 3).
furnished an optimized 84% yield of b-aminoester 23 when
1.3 equiv of AcOH and a 20-fold excess of ethyl acrylate were
employed.
Compound 23 was uneventfully converted (92% yield) into the
related sulfonamido derivative 24 by reaction with tosyl chloride
and DIPEA in refluxing chloroform. However, attempts to cyclize
the sulfonamido ester [SnCl4, polyphosphoric ester (PPE), PPA]20
met with failure, leading to decomposition products, such as the
known detosylated compound 25,21a which was isolated in 20%
yield when PPA was employed as cyclizing agent.20d Therefore, the
ester was subjected to basic hydrolysis to obtain sulfonamido acid
26. Not unexpectedly, important quantities of the known sulfon-
amide 27,21b the retro-Michael side-product of 25, were isolated
irrespective of the nature of the base employed; however, the use of
LiOH in THF–H2O furnished 26 in 76% yield, accompanied by only
20% of 27.
The cyclization of acid 26 was next studied. Unfortunately, when
Lewis acid-mediated cyclization of the acid chloride was attempted
(PCl5, benzene, reflux, followed by AlCl3 at 0 ꢁC or SOCl2 in 1,2-di-
chloroethane under reflux, followed by SnCl4, at 0 ꢁC), compound
2521 was isolated as the major product in up to 70% yield accom-
panied with only 10–15% of 28 (Table 1). On the other hand, cy-
clization with POCl3 in refluxing toluene furnished only 21% of the
desired quinolin-4-one 28 and reaction with P2O5 lead to recovery
of the previously observed retro-Michael product 27 in 45% yield
and the isolation of 23% of the expected quinolin-4-one derivative
28. However, when acid 26 was subjected to reaction with excess
PPE in toluene at 55 ꢁC, a smooth and clean cyclization took place,
allowing the isolation of 28 in 95% yield after 2 h.
5
CO2Et
4
6
1
a
c
MeO
NHR
MeO
d
N
MeO
3
CO2H
2
OMe
OMe R
OMe
22 R= CO2Et
19 R= H
23 R= H
24 R= Ts
b
21
e
O
5
4
3
4a
CO2H
6
7
f
+
2
H
MeO
8a
N
1
MeO
N
MeO
N
8
OMe R
OMe Ts
OMe Ts
28 R= Ts
25 R= H
26
27
Scheme 3. (a) (PhO)2P(O)N3, EtOH, Et3N, THF, 65 ꢁC, 2 h (90%); (b) KOH, EtOH, reflux,
overnight (97%); (c) H2C]CHCO2Et, AcOH (cat.), reflux, 24 h (84%); (d) TsCl, iPr2NEt,
CHCl3, reflux,14 h (92%); (e) (1) 10% LiOH, EtOH–H2O, reflux 24 h; (2) HCl, pH¼3 (26, 74%;
27, 20%); (f) PPA, 90 ꢁC, overnight (25, 20%þ26, 48%), PPE, PhMe, 55 ꢁC, 2 h (28, 95%).
Having secured the access to key intermediate 28, formation of
the third ring was undertaken, as shown in Scheme 4. To that end,
the quinolin-4-one was subjected to a reductive amination with
aminoacetal and sodium cyanoborohydride as selective reducing
agent,20 with disappointing initial results.
Next, 19 was submitted to an aza-Michael addition by reaction
with refluxing ethyl acrylate under acetic acid promotion; this
Table 1
Optimization of the cyclization of acid 26
O
CO2H
Conditions
+
H
MeO
N
MeO
N
MeO
N
OMe R
OMe
OMe Ts
Ts
26
28 R= Ts
25 R= H
27
Reagent
Equiv
Solvent
Temp (ꢁC)
28 (%)
25 (%)
Other (%)
1. PCl5
2. AlCl3
1. SOCl2
2. SnCl4
1. SOCl2
2. SnCl4
P2O5
POCl3
PPE
PPE
1.2
2.1
33
2
5
2
Benzene
1,2-DCE
Reflux
Reflux
0
Reflux
0
Reflux
Reflux
Reflux
55
15
10
23
70
d
CHCl3
26 (60)
Benzene
Xylene
Toluene
Toluene
Toluene
10
23
21
10
d
d
2
5
27 (45)
d
20a
20a
Decomposition
95
d
d
a
Expressed as mg PPE/mg substrate.

E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
5239
MeO
OMe
R1
R2
Ts
H
R
N
N
N
O
a
f
MeO
MeO
MeO
N
MeO
N
OMe Ts
OMe Ts
OMe Ts
d
28
30 R= Ts
29 R= H
34 R= Ns
33a R1= H, R2= OMe
33b R1= OMe, R2= H
33c R1= OH, R2= H
33d R1= H, R2= OH
b
c
g
h
N
OMe Ts
e
R1
R2
31
Ns
H
H
N
N
Ts
OHC
N
MeO
N
MeO
N
OMe Ts
OMe H
MeO
N
35a R1= H, R2= OMe
35b R1= OMe, R2= H
35c R1= H, R2= OH
35d R1= OH, R2= H
18
OMe Ts
32
i
i
Scheme 4. (a) (1) H2NCH2CH(OMe)2, AcOH, MgSO4, 4 Å MS, EtOH, overnight; (2) NaCNBH3, reflux, 24 h (87%); (b) TsCl, Pr2NEt, CHCl3, reflux, 14 h (64%); (c) NsCl, Pr2NEt, CHCl3,
reflux, 14 h (20%); (d) 6 N HCl (6 equiv), dioxane, EtOH, reflux, 2 h (94%) or BF $Et O, CH Cl , rt, 12 h (47%); (e) ZnI , CH Cl , , rt, 24 h (54%); (f) SnCl , CH Cl , ꢀ78 ꢁC, 1.5 h, ꢀ60 ꢁ
C
)))
3
2
2
2
2
2
2
4
2
2
overnight (31, 23%; 32 (4%); 33a, 9%; 33b, 24%; 33c, 9%); (g) SnCl4, CH2Cl2, ꢀ78 ꢁC, 1.5 h, ꢀ60 ꢁC overnight (35a, 18%; 35b, 18%; 35c, 16%; 35d, 22%); (h) (1) Na, NH3, ꢀ33 ꢁC; (2) NH4Cl
(83%).
It is known that aromatic ketones bearing activating sub-
stituents in the ortho/para positions react sluggishly with amines to
form the corresponding imines, thus furnishing poor yields of the
reductive amination products.22 However, it was observed that
yields increased when the carbonyl compound was left to react
overnight with the amine in the presence of activated 4 Å molec-
ular sieves before adding the reducing agent, this strategy fur-
nished secondary amine 29 in an optimized 87% yield.
Amine 29 was then submitted to sulfonamidation with tosyl
chloride and DIPEA under forcing conditions, yielding sulfonami-
doacetal 30 in 64% yield and setting the stage for the cyclization
step. The moderate yield attained is perhaps due to steric hin-
drance, which in related cases has forced to change the strategy for
the introduction of the sulfonamidoacetal moiety.23a,b Reaction of
30 under modified Jackson24a conditions (6 N HCl, dioxane, EtOH,
reflux)23 did not afford the expected tricyclic product, cleanly fur-
nishing instead an almost quantitative yield of 1,2-dihydroquino-
line derivative 31, resulting from the acid promoted elimination of
the sulfonamidoacetal side chain. Analogously, 47% of 31 together
with 48% of aldehyde 32 were isolated when cyclization of 30 was
attempted under BF3$Et2O promotion.
the optimization of the cyclization conditions of 30 are shown in
Table 2.
Complete and unequivocal attribution of the proton and carbon
atoms of 33a–c was performed with the aid of 2D NMR experi-
ments, while the coupling constants of H-6 allowed assignment of
the relative stereochemistry of the alcohol and ether moieties at-
tached to C-6.
In these cyclizations, it has been recognized that the stabilizing
effect of the sulfonamido group24 is due to its electron-withdraw-
ing characteristics. Therefore, in view of the meager yields of the
cyclization, the performance of the nosyl protecting group was
explored.23b Thus, amine 29 was submitted to reaction with nosyl
chloride and DIPEA in refluxing chloroform; unexpectedly, how-
ever, the reaction did not proceed to completion even after pro-
longed reflux, furnishing only 20% of nosylamide 34. However,
when nosylamide 34 was submitted to cyclization with SnCl4,
cyclized products 35a–d were isolated in 74% combined yield.
Structural elucidation of the tricyclic sulfonamides 35 was car-
ried out through a combination of NMR experiments and compar-
isons with the spectra of 33a–c. Encouraged by the better
performance of 34 in the critical cyclization step, alternative con-
ditions for the introduction of the 4-nitrosulfonamide moiety were
explored; however, these resulted unsuccessful, favoring the
tosylamide route as a strategy toward the target. Therefore, taking
into account the use of sodium in liquid ammonia for the removal of
benzyl and tosyl protecting groups,26 the mixture of tricyclic
compounds 33 was subjected to reductive desulfonylation with
concomitant deoxygenation of the benzylic position with this re-
agent combination, furnishing the expected 2,3,3a,4,5,6-hexahy-
droaaptamine 18 in 83% yield.
This unwanted but not fully unexpected outcome could be the
result of the improper activation of the aromatic ring, due to the
ortho-disubstituted nature of the methoxy group located para to
the ring closure position. These steric effects are reflected in an out-
of-plane preferred conformation of the 8-methoxy group of acetal
30, which was evident in its 13C NMR spectrum, when compared
with the chemical shift of the neighboring 8-methoxy moiety (d
C
OMe-7¼55.91; d OMe-8¼59.58). ZnI2 catalysis did not afford
C
better results, being the aldehyde 32 isolated as the major product,
in 54% yield. Fortunately, however, use of SnCl4 at ꢀ60 ꢁC provided
a mixture of methyl ethers 33a,b and alcohols 33c,d in 42% com-
bined yield, accompanied by 23% of compound 31 and 4% of alde-
hyde 32.25 Although pure samples of 33d could not been obtained,
some of its most distinctive signals were observed in the 1H NMR
spectrum of its mixture with 33c. These included a singlet at d 6.99
and a doublet of doublets resonating at d 4.42 (H-3a). The results of
In conclusion, a formal total synthesis of the marine alkaloid
aaptamine (1) was achieved through the development of a new
strategy to obtain the previously known 2,3,3a,4,5,6-hexahy-
droaaptamine (18). This alternative access of 18 was accomplished
in eight steps and 11% overall yield from aniline derivative 19,
employing an AC/B ring forming strategy, with quinolin-4-one 28
as key intermediate.

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E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
Table 2
Optimization of the cyclization of sulfonamidoacetal 30
MeO
OMe
Ts
H
R
N
R
Ts
N
OHC
N
N
Cond.
+
+
MeO
N
MeO
N
MeO
N
MeO
OMe Ts
OMe Ts
OMe Ts
OMe Ts
31
32
29 R= H
33a R= α-OMe
33b R= β-OMe
33c R= β-OH
30 R= Ts
Reagent (equiv)
Solvent
Temp (ꢁC)
Time (h)
33a–c (%)
31 (%)
32 (%)
6 N HCl (6), EtOH (10)
BF3$Et2O (3)
PPA, PPE (10)a
ZnI2 (2)
Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
6 N HCl
CH2Cl2
CH2Cl2
Reflux
rt
rt
2
12
12
24
12
12
24
12
12
0
0
0
94
47
56
0
48
0
54
ND
ND
0
rt,
<5
0
))))
TiCl4 (2)
ꢀ78
ꢀ78
rt
<10
<10
<10b
30c
42c,e
ND
ND
d
TMSOTf (2)
HCl (excess)
SnCl4 (2)
ꢀ40
<10
23
<10
4
SnCl4 (2)
ꢀ78d
ND¼Not determined.
a
Water (1 equiv) was added to PPE.
b
Bobbitt reaction with aminoacetal 29.22b
c
As a mixture of diastereomeric alcohols and methyl ethers.
d
e
1.5 h at ꢀ78 ꢁC and then overnight at ꢀ60 ꢁC.
Overall yield; a mixture of 33a (9%), 33b (24%), and 33c (9%) was isolated.
3. Experimental
compounds, elution was carried out in the gradient of solvent po-
larity mode, with different mixtures of hexane–EtOAc, followed by
EtOAc–EtOH, employing 0.75–1 atm of compressed air in order to
accelerate the eluting flow. All new compounds gave single spots on
TLC plates run in different hexane–EtOAc and CH2Cl2–toluene sol-
vent systems. Chromatographic spots were detected by exposure to
UV light (254 nm) followed by spraying with ethanolic p-anis-
aldehyde/sulfuric acid reagent and careful heating of the plates for
better selectivity.
3.1. General conditions
Melting points were taken on an Ernst Leitz Wetzlar model 350
hot-stage microscope apparatus and are informed uncorrected.
FTIR spectra were determined with a Shimadzu Prestige 21 spec-
trophotometer as thin films held between NaCl cells or as solid
dispersions in KBr disks. The 1H and 13C NMR spectra were acquired
in CDCl3 employing TMS as internal standard, with a Bruker Avance
300 apparatus (300.13 and 75.48 MHz, for 1H and 13C, respectively).
The chemical shifts are consigned in parts per million downfield
from TMS, as the internal standard. DEPT 135 and DEPT 90 aided
the interpretation and assignment of the fully decoupled 13C NMR
spectra. In special cases, 2D NMR experiments (COSY, HSQC, HMBC,
3.2. 2,3-Dimethoxyphenylamine 19
To a solution of 2,3-dimethoxybenzoic acid (21, 1000 mg,
5.49 mmol) in dry THF (20 mL) were added diphenylphosphoryl
azide (1586 mg, 5.76 mmol), absolute ethanol (3.2 mL, 55 mmol),
and anhydrous Et3N (0.92 mL, 6.58 mmol). The mixture was stirred
at 65 ꢁC for 2 h, being observed a strong evolution of gas. After
cooling to room temperature, the reaction was concentrated under
reduced pressure in order to remove most of the ethanol, and then
it was diluted with EtOAc (20 mL); the organic phase was succes-
sively washed with saturated aqueous NaHCO3 solution, water,
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuum. The concentrate was purified by flash chromatography to
give 22 (1113 mg, 90%), as an oil.17a,b IR (film, n): 3372, 2978, 1735,
NOE, and ROESY) were also employed. Symbols such as asterisk ( )
*
and number sign (#) indicate that assignments may be exchanged
among each set of marked resonances. Pairs of diastereotopic
protons designated as ‘uf’ and ‘df’ mean the most upfield (shielded)
and downfield (deshielded) signal, respectively, by extension of the
nomenclature employed in these cases by Culvenor and co-
workers.27 Proton and carbon signals belonging to tosyl/nosyl
groups are designated as ‘ArH’ and ‘TsC/NsC’, respectively. High-
resolution mass spectral data were obtained from the Laboratory of
Glycochemistry and Asymmetric Synthesis (LGSA) of EPFL, Lau-
sanne, Switzerland and Kent Electronics, Kent, UK. The reactions
were carried out under positive pressure of dry Nitrogen or Argon,
employing oven-dried glassware.
1608, 1535, 1478, 1300, 1258, 1169, 1050, 998, and 782 cmꢀ1 1H
;
NMR (d): 1.32 (t, 3H, J¼7.1 Hz, OCH2Me), 3.85 (s, 3H, OMe), 3.86 (s,
3H, OMe), 4.23 (q, 2H, J¼7.1 Hz, OCH2Me), 6.61 (dd, 1H, J¼1.3,
8.3 Hz, H-4), 7.02 (t, 1H, J¼8.3 Hz, H-5), 7.26 (br s, 1H, w1/2¼7 Hz,
NH), and 7.73 (dd, 1H, J¼1.3, 8.3 Hz, H-6); 13C NMR (d): 14.5
(CH2Me), 55.8 (OMe-3), 60.6 (OMe-2), 61.2 (CH2Me), 106.5 (C-4),
The standard work-up procedure, depending of the reaction
medium, consisted in diluting the reaction with brine (5–20 mL)
and extracting the reaction products with EtOAc or CH2Cl2
(3ꢂ20–40 mL); the combined organic extracts were washed once
with brine (5–10 mL), dried over Na2SO4, and concentrated under
reduced pressure. The respective residues were flash
chromatographed.
Flash column chromatographies were carried out with silica gel
60 H. Samples were pre-adsorbed on coarse grain silica gel and
loaded as free flowing powders. For the separation of all
110.9 (C-6), 124.2 (C-5), 132.3 (C-1), 137.0 (C-2), 152.1 (C]O)
*
, and
153.5 (C-3) To solution of ethyl carbamate 22 (1.236 g,
*
.
a
5.49 mmol) in ethanol (10 mL), was added a freshly prepared so-
lution of potassium hydroxide (3250 mg, 58 mmol) in ethanol
(20 mL). The mixture was refluxed overnight, and after assessment
(by TLC) of absence of starting material, it was cooled to room
temperature and concentrated under reduced pressure. The
resulting oily residue was diluted with EtOAc, washed with brine,

E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
5241
dried over Na2SO4, and concentrated under vacuum. The dark
brownish oil so obtained was purified by flash chromatography
giving 2,3-dimethoxyaniline 19 (812 mg, 97%), as an orange oil. IR
(film, n): 3447, 3371, 2937, 1612, 1477, 1321, 1264, 1131, 1087, and
732 cmꢀ1; 1H NMR (d): 2.90–3.93 (br s, 2H, NH2), 3.82 (s, 3H, OMe),
3.84 (s, 3H, OMe), 6.34 (dd, 1H, J¼1.4, 8.1 Hz, H-6), 6.39 (dd, 1H,
J¼1.4, 8.1 Hz, H-4), and 6.84 (t, 1H, J¼8.1 Hz, H-5); 13C NMR (d): 55.7
(OMe-3), 59.8 (OMe-2), 102.3 (C-4), 108.8 (C-6), 124.2 (C-5), 136.0
(C-1), 140.7 (C-2), and 153.1 (C-3). These data were in agreement
with the literature.17
8.4 Hz, H-6), 6.96 (t, 1H, J¼8.4 Hz, H-5), 7.14 (br s, 1H, w1/2¼7 Hz,
NH), 7.19 (dd, 1H, J¼1.2, 8.4 Hz, H-4), 7.21 (d, 2H, J¼8.2 Hz, ArH-3
and ArH-5 of Ts), and 7.69 (d, 2H, J¼8.2 Hz, ArH-2 and ArH-6 of Ts);
13C NMR (d): 21.7 (ArMe of Ts), 56.0 (OMe-2), 60.6 (OMe-3), 114.9
(C-4), 122.6 (C-6), 124.2 (C-5), 127.7 (C-1), 129.1 (2C, TsC-2 and TsC-
6)
*
, 129.3 (2C, TsC-3 and TsC-5) , 137.1 (TsC-1), 144.7 (TsC-4), 148.5
*
(C-2), and 153.4 (C-3); CIMS, m/z (%): 308 (MHþ, 16), 307 (Mþ, 9),
278 (MHþꢀH2CO, 5), 153 (MHþꢀTs, 84), 137 (MþꢀTsꢀMe, 50), 123
(MHþꢀTsꢀH2CO, 100), 110 (19), and 91 (PhMeþ, 85). Increasing
solvent polarity furnished acid 26 (694 mg, 76%), as a white solid,
mp 143–144 ꢁC (hexane–EtOAc). IR (KBr, n): 3600–2600, 3430,
3.3. 3-[(2,3-Dimethoxyphenyl)-(toluene-4-sulfonyl)-amino]-
propionic acid ethyl ester 24
2949, 1718, 1584, 1432, 1339, 1262, 1161, 1038, 995, and 746 cmꢀ1
;
1H NMR (d): 2.42 (s, 3H, ArMe of Ts), 2.58 (t, 2H, J¼7.6 Hz, CH2CO2H),
3.72 (s, 3H, OMe-2), 3.84 (t, 2H, J¼7.6 Hz, NCH2), 3.85 (s, 3H, OMe-
3), 6.27 (br s, w1/2¼9 Hz, OH), 6.62 (dd, 1H, J¼2.0, 8.3 Hz, H-6), 6.90
(dd, 1H, J¼2.0, 8.3 Hz, H-4), 6.95 (t, 1H, J¼8.3 Hz, H-5), 7.28 (d, 2H,
J¼8.2 Hz, ArH-3 and ArH-5 of Ts), and 7.68 (d, 2H, J¼8.2 Hz, ArH-2
and ArH-6 of Ts); 13C NMR (d): 21.5 (ArMe of Ts), 33.6 (CH2CO2H),
46.5 (ArNCH2), 55.9 (OMe-3), 60.8 (OMe-2), 113.1 (C-4), 122.7 (C-
Acetic acid (50 mL) was added to 2,3-dimethoxyaniline (19,
100 mg, 0.63 mmol) in ethyl acrylate (2 mL) and the mixture was
refluxed 24 h. The resulting red solution was carefully evaporated
under reduced pressure and the residue was flash chromato-
graphed, furnishing 23 (165 mg, 84%), as an oil. IR (film, n): 3405,
2967, 1731, 1602, 1513, 1481, 1263, 1130, and 1005 cmꢀ1
;
1H NMR
5)
*
, 123.2 (C-6) , 127.7 (2C, TsC-2 and TsC-6), 129.5 (2C, TsC-3 and
*
(d): 1.26 (t, 2H, J¼7.1 Hz, CH2Me), 2.61 (t, 2H, J¼6.5 Hz, CH2CO2Et),
3.47 (t, 2H, J¼6.5 Hz, NCH2), 3.78 (s, 3H, OMe), 3.84 (s, 3H, OMe),
4.15 (q, 2H, J¼7.1 Hz, OCH2Me), 4.59 (br s, 1H, w1/2¼30 Hz, NH), 6.32
TsC-5), 131.8 (C-1), 137.2 (TsC-1), 143.4 (TsC-4), 147.6 (C-2), 153.5 (C-
3), and 176.2 (C]O); HRMS (TOF MS ESIþion mode) calcd for
C
18H21NO6SNa: 402.0988 (MþNa)þ; found: 402.0988.
(dd, 1H, J¼1.2, 8.2 Hz, H-6)
*
, 6.34 (dd, 1H, J¼1.2, 8.2 Hz, H-4)
*
, and
6.92 (t, 1H, J¼8.2 Hz, H-5); 13C NMR (d): 14.2 (OCH2Me), 34.3
(CH2CO2Et), 39.3 (ArNCH2), 55.7 (OMe-3), 59.8 (OMe-2), 60.6
(OCH2Me), 101.5 (C-4), 104.24 (C-6), 124.4 (C-5), 135.7 (C-1), 141.8
(C-2), 152.6 (C-3), and 172.2 (C]O). To a stirred solution of amine
23 (144 mg, 0.57 mmol) in dry chloroform (3 mL) at 0 ꢁC, were
added DIPEA (0.15 mL, 0.86 mmol) and tosyl chloride (135 mg,
0.71 mmol). The mixture was allowed to reach room temperature
after 15 min and then refluxed until consumption of the starting
amine (by TLC, 14–20 h). The reaction was allowed to attain room
temperature, concentrated in vacuum, and the residue was chro-
matographed, rendering sulfonamide 24 (213 mg, 92%), as an oil. IR
(film, n): 2943, 1734, 1587, 1474,1347, 1270,1160, and 1096 cmꢀ1; 1H
NMR (d): 1.17 (t, 3H, J¼7.1 Hz, CH2Me), 2.42 (s, 3H, ArMe of Ts), 2.54
(t, 2H, J¼7.5 Hz, CH2CO2Et), 3.70 (s, 3H, OMe-2), 3.84 (s, 3H, OMe-3),
3.85 (t, 2H, J¼7.5 Hz, NCH2), 4.01 (q, 2H, J¼7.1 Hz, OCH2Me), 6.63
(dd, 1H, J¼2.1, 8.3 Hz, H-6), 6.89 (dd, 1H, J¼2.1, 8.3 Hz, H-4), 6.94 (t,
1H, J¼8.3 Hz, H-5), 7.28 (d, 2H, J¼8.4 Hz, ArH-3 and ArH-5 of Ts),
and 7.68 (d, 2H, J¼8.4 Hz, ArH-2 and ArH-6 of Ts); 13C NMR (d): 14.1
(OCH2Me), 21.5 (ArMe of Ts), 34.1 (CH2CO2Et), 46.8 (ArNCH2), 55.9
3.5. 7,8-Dimethoxy-2,3-dihydro-1H-quinolin-4-one 25
A mixture of 26 (20 mg, 0.049 mmol) and PPA (400 mg,
20 equiv) was heated overnight at 90 ꢁC; the reddish mixture was
then treated with 10% NaHCO3 (2 mL) and the organic products
were extracted with EtOAc (4ꢂ15 mL) the combined extracts were
dried over Na2SO4, concentrated under reduced pressure, and
chromatographed. Starting material 26 (9.6 mg, 48%) was re-
covered. Increasing solvent polarity furnished 25 (2 mg, 20%), as
a solid, mp 90–92 ꢁC (hexane–EtOAc; lit.21 92 ꢁC). 1H NMR (d): 2.67
(t, 2H, J¼6.9 Hz, H-3), 3.57 (t, 2H, J¼6.9 Hz, H-2), 3.83 (s, 3H, OMe-
8), 3.90 (s, 3H, OMe-7), 4.91 (br s, 1H, w1/2¼8 Hz, NH), 6.39 (d, 1H,
J¼8.8 Hz, H-6), and 7.64 (d, 1H, J¼8.8 Hz, H-5); 13C NMR (d): 37.9
(C-3), 42.1 (C-2), 55.9 (OMe-7), 60.1 (OMe-8), 102.5 (C-6), 114.8
(C-5), 124.1 (C-4a), 134.2 (C-8a), 146.8 (C-8), 156.7 (C-7), and 192.7
(C-4).
(OMe-3), 60.5 (OCH2Me), 60.8 (OMe-2), 113.0 (C-4), 122.9 (C-5)
*
,
3.6. 7,8-Dimethoxy-1-(toluene-4-sulfonyl)-2,3-dihydro-
123.0 (C-6) , 127.7 (2C, TsC-2 and TsC-6), 129.5 (2C, TsC-3 and TsC-
*
1H-quinolin-4-one 28
5), 131.9 (C-1), 137.4 (TsC-1), 143.2 (TsC-4), 147.6 (C-2), 153.5 (C-3),
and 171.2 (C]O); HRMS (TOF MS ESIþion mode) calcd for
To a solution of acid 26 (96 mg, 0.25 mmol) in toluene (6 mL)
was added recently prepared PPE28 (1.4 mL), and the resulting
homogeneous mixture was heated at 55 ꢁC for 2 h. Crushed ice
(10 g) was then carefully added, and extraction of the products was
carried out with EtOAc (4ꢂ10 mL). The organic phase was washed
with brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was chromatographed to afford
quinolin-4-one 28 (70 mg, 95%), as a white solid, mp 128–129 ꢁC
(hexane–EtOAc). IR (KBr, n): 2966, 2848, 1682, 1593, 1458, 1359,
1207, 1181, 1090, 963, 801, 706, and 668 cmꢀ1; 1H NMR (d): 2.45 (s,
3H, ArMe of Ts), 2.81 (t, 2H, J¼6.3 Hz, H-3), 3.48 (s, 3H, OMe-8), 3.93
(s, 3H, OMe-7), 4.09 (t, 2H, J¼6.3 Hz, H-2), 6.88 (d, 1H, J¼8.9 Hz, H-
6), 7.32 (d, 2H, J¼8.0 Hz, ArH-3 and ArH-5 of Ts), 7.79 (d, 1H,
J¼8.9 Hz, H-5), and 7.86 (d, 2H, J¼8.0 Hz, ArH-2 and ArH-6 of Ts);
13C NMR (d): 21.6 (ArMe of Ts), 38.5 (C-3), 47.7 (C-2), 56.1 (OMe-7),
60.1 (OMe-8), 110.1 (C-6), 122.6 (C-5), 123.9 (C-4a), 127.2 (2C, TsC-2
and TsC-6), 129.5 (2C, TsC-3 and TsC-5), 136.5 (TsC-1), 141.1 (C-8),
C
13H20NO4: 254.1392; found: 254.1393.
3.4. 3-[(2,3-Dimethoxyphenyl)-(toluene-4-sulfonyl)-amino]-
propionic acid 26
To a suspension of ester 24 (978 mg, 2.4 mmol) in an EtOH–H2O
mixture (3:1, 5 mL), was carefully added a 10% solution of LiOH
(1.8 mL) and the system was heated at reflux for 24 h. Then, the
reaction was cooled to room temperature acidified to pH¼3–4 with
1 M HCl; the ethanol was cautiously removed under reduced
pressure and the remaining aqueous suspension was extracted
with EtOAc (4ꢂ10 mL). The combined organic fractions were dried
over Na2SO4 and concentrated under reduced pressure, leaving
a residue, which was purified by column chromatography. The side-
product 27 was isolated (154 mg, 20%), as a colorless solid, mp 155–
157 ꢁC (hexane–EtOAc) or 108–110 ꢁC (EtOH; lit.21b 109 ꢁC, EtOH).
IR (film, n): 3422, 3262, 2917, 2849, 1599, 1443, 1384, 1297, 1118,
1043, 965, 814, 745, and 665 cmꢀ1; 1H NMR (d): 2.36 (s, 3H, ArMe of
Ts), 3.57 (s, 3H, OMe-2), 3.80 (s, 3H, OMe-3), 6.62 (dd, 1H, J¼1.2,
143.6 (TsC-4)
*
, 143.9 (C-8a) , 158.3 (C-7), and 192.7 (C-4); HRMS
*
(TOF MS ESIþion mode) calcd for
C18H19NO5SNa: 384.0882
(MþNa)þ; found: 384.0886.

5242
E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
3.7. (2,2-Dimethoxyethyl)-[7,8-dimethoxy-1-(toluene-
4-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-amine 29
3.9. N-(2,2-Dimethoxyethyl)-N-[7,8-dimethoxy-1-(toluene-
4-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-4-nitro-
benzenesulfonamide 34
Aminoacetaldehyde dimethylacetal (360 mL, 3.5 mmol) and
glacial acetic acid (110 mL, 2.44 mmol) were successively added to
a suspension of quinolin-4-one 28 (233 mg, 0.65 mmol), MgSO4
(300 mg), and activated 4 Å molecular sieves (300 mg) in abso-
lute EtOH (10 mL). The mixture was stirred overnight at room
temperature, then NaCNBH3 (53 mg, 0.84 mmol) was carefully
added. The resulting slurry was refluxed for 24 h, then cooled to
room temperature and after removal of the volatiles in vacuum,
the remaining solid was directly purified by column chroma-
tography, furnishing the expected amine 29 (254 mg, 87%), as an
oil. IR (film, n): 2934, 2835, 1601, 1495, 1335, 1157, 1094, and
To a cooled solution of amine 29 (57 mg, 0.12 mmol) in anhy-
drous CHCl3 (2 mL) were successively added DIPEA (46 mL,
0.36 mmol) and nosyl chloride (42 mg, 0.19 mmol). The suspension
was heated under reflux until consumption of the starting material
(by TLC). The flask was cooled to room temperature and most of the
organic solvent was removed in the rotary evaporator, leaving an
oily residue, which was purified by chromatography to afford the
nosylamide 34 (15 mg, 20%). IR (film, n): 2926, 2855, 1604, 1530,
1496, 1350, 1294, 1158, 1088, 953, and 735 cmꢀ1; 1H NMR (d): 2.05–
2.15 (m, 1H, H-3uf), 2.40–2.51 (m, 1H, H-3df), 2.42 (s, 3H, ArMe of
760 cmꢀ1
;
1H NMR (d): 2.15–2.40 (m, 1H, H-3uf), 2.44 (s, 3H,
Ts), 3.19 (s, 3H, acetal-OMe)
*
, 3.20 (s, 3H, acetal-OMe)
*
, 3.21 (s, 3H,
ArMe of Ts), 2.80 (dd, 1H, J¼5.3, 12.0 Hz, CH2CH(OMe)2), 2.87 (dd,
1H, J¼5.0, 12.0 Hz, CH2CH(OMe)2), 3.40 (s, 6H, 2ꢂacetal-OMe),
3.47 (s, 3H, OMe-8), 3.45–3.65 (m, 1H, H-3df), 3.70–3.85 (m, 1H,
H-2uf), 3.86 (s, 3H, OMe-7), 3.97–4.17 (m, 2H, H-2df and H-4),
3.98 (br s, w1/2¼9 Hz, NH), 4.52 (dd, 1H, J¼5.0, 5.3 Hz,
CH(OMe)2), 6.85 (d, 1H, J¼8.5 Hz, H-6), 7.10 (d, 1H, J¼8.5 Hz, H-5),
7.33 (d, 2H, J¼8.5 Hz, ArH-3 and ArH-5 of Ts), and 7.90 (d, 2H,
J¼8.5 Hz, ArH-2 and ArH-6 of Ts); 13C NMR (d): 21.6 (ArMe of Ts),
OMe-8)
*
, 3.29 (dd, 1H, J¼5.4, 15.2 Hz, CH2CH(OMe)2), 3.43 (dd, 1H,
J¼4.9, 15.2 Hz, CH2CH(OMe)2), 3.40–3.52 (m, 1H, H-2uf), 3.81 (s, 3H,
OMe-7), 3.99 (dt, 1H, J¼4.1, 13.8 Hz, H-2df), 4.32 (dd, 1H, J¼4.9,
5.4 Hz, CH(OMe)2), 5.24 (t, 1H, J¼8.8 Hz, H-4), 6.69 (d, 1H, J¼8.8 Hz,
H-6), 6.77 (d, 1H, J¼8.8 Hz, H-5), 7.30 (d, 2H, J¼8.5 Hz, ArH-3 and
ArH-5 of Ts), 7.84 (d, 2H, J¼8.5 Hz, ArH-2 and ArH-6 of Ts), 8.09 (d,
2H, J¼8.8 Hz, ArH-2 and ArH-6 of Ns), and 8.37 (d, 2H, J¼8.8 Hz,
ArH-3 and ArH-5 of Ns); 13C NMR (d): 21.5 (ArMe of Ts), 29.3 (C-3),
29.9 (C-3), 44.2 (C-2), 47.7 (NCH2), 53.2 (C-4)
*
, 54.5 (acetal-
47.0 (C-2)#, 47.1 (NCH2)#, 54.2 (C-4)
etal-OMe) , 56.0 (OMe-7), 59.6 (OMe-8), 102.6 (acetal), 110.1 (C-6),
*
, 54.3 (acetal-OMe) , 54.8 (ac-
*
OMe) , 54.6 (acetal-OMe) , 56.0 (OMe-7), 60.1 (OMe-8), 102.7
*
*
*
(acetal), 110.7 (C-6), 123.4 (C-5), 123.5 (C-4a), 127.4 (2C, TsC-2 and
TsC-6), 129.4 (2C, TsC-3 and TsC-5), 131.3 (C-8a), 137.8 (TsC-1),
143.5 (TsC-4)#, 144.5 (C-8)#, and 153.1 (C-7); HRMS (TOF MS
ESIþion mode) calcd for C22H31N2O6S: 451.1903 (Mþ1)þ; found:
451.1901.
121.8 (C-5), 123.9 (C-4a), 124.2 (2C, NsC-3 and NsC-5), 126.8 (2C,
TsC-2 and TsC-6), 128.6 (2C, NsC-2 and NsC-6), 129.2 (2C, TsC-3 and
TsC-5), 133.2 (C-8a), 139.2 (TsC-1), 143.0 (NsC-1), 143.6 (C-8), 146.9
(TsC-4), 149.9 (NsC-4), and 152.6 (C-7); HRMS (TOF MS ESIþion
mode) calcd for C28H33N3O10S2Na: 658.1505 (MþNa)þ; found:
658.1512.
3.10. Attempt of cyclization of tosylacetal 30 under modified
Jackson conditions. Isolation of 7,8-dimethoxy-1-(toluene-
4-sulfonyl)-1,2-dihydroquinoline 31
3.8. N-(2,2-Dimethoxyethyl)-N-[7,8-dimethoxy-1-(toluene-
4-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-4-methyl-
benzenesulfonamide 30
EtOH (0.22 mL) and 6 N HCl (0.23 mL) were successively added
to a cold solution of tosylacetal 30 (121 mg, 0.20 mmol) in dioxane
(1 mL) and the resulting solution submitted to reflux until complete
disappearance of the starting material (30 min). The reaction was
then diluted with EtOAc (25 mL) and successively washed with
brine (5 mL) containing 10% Na2CO3 (0.5 mL) and brine (5 mL). The
organic phase was dried over Na2SO4, concentrated under reduced
pressure, and chromatographed, furnishing 31 (65 mg, 94%), as an
oil. IR (film, n): 2923, 2853, 1597, 1491, 1350, 1266, 1160, 1090, 809,
To a cooled solution of amine 29 (96 mg, 0.21 mmol) in anhy-
drous CHCl3 (5 mL) were successively added DIPEA (74 mL,
0.43 mmol) and tosyl chloride (52 mg, 0.38 mmol). The suspension
was heated under reflux overnight until consumption of the
starting material (by TLC). The flask was cooled to room tempera-
ture and most of the organic solvent was removed in the rotary
evaporator, leaving an oily residue, which was purified by chro-
matography to afford the tosylamide 30 (82 mg, 64%), as a solid, mp
169–170 ꢁC (hexane–EtOAc). IR (KBr, n): 2926, 2854, 1600, 1496,
and 674 cmꢀ1 1H NMR (d): 2.39 (s, 3H, ArMe of Ts), 3.87 (s, 3H,
;
1338, 1292, 1157, and 668 cmꢀ1 1H NMR (d): 1.97–2.10 (m, 1H, H-
;
OMe), 3.88 (s, 3H, OMe), 4.26 (br s, 2H, H-2), 5.51 (dt, 1H, J¼4.0,
9.7 Hz, H-3), 6.05 (dt, 1H, J¼1.5, 9.7 Hz, H-4), 6.67 (d, 1H, J¼8.2 Hz,
H-6), 6.78 (d, 1H, J¼8.2 Hz, H-5), 7.16 (d, 2H, J¼8.5 Hz, ArH-3 and
3uf), 2.28–2.42 (m, 1H, H-3df), 2.42 (s, 3H, ArMe of 1-Ts), 2.45 (s, 3H,
ArMe of 4-NTs), 3.17 (s, 3H, acetal-OMe), 3.19 (s, 3H, OMe-8), 3.20
(dd, 1H, J¼5.9, 15.1 Hz, CH2CH(OMe)2), 3.24 (s, 3H, acetal-OMe),
3.29 (dd, 1H, J¼4.7, 15.1 Hz, CH2CH(OMe)2), 3.45–3.57 (m, 1H, H-
2uf), 3.81 (s, 3H, OMe-7), 3.93 (dt, 1H, J¼4.5, 13.9 Hz, H-2df), 4.44
(dd, 1H, J¼4.7, 5.9 Hz, CH(OMe)2), 5.12 (t, 1H, J¼8.5 Hz, H-4), 6.70 (d,
1H, J¼8.9 Hz, H-6), 6.87 (d, 1H, J¼8.9 Hz, H-5), 7.29 (d, 2H, J¼8.5 Hz,
ArH-3 and ArH-5 of 1-Ts), 7.32 (d, 2H, J¼8.5 Hz, ArH-3 and ArH-5 of
4-NTs), 7.77 (d, 2H, J¼8.5 Hz, ArH-2 and ArH-6 of 4-NTs), and 7.82
(d, 2H, J¼8.5 Hz, ArH-2 and ArH-6 of 1-Ts); 13C NMR (d): 21.5 (ArMe
of Ts), 21.6 (ArMe of Ts), 28.9 (C-3), 46.7 (NCH2), 46.9 (C-2), 53.5
(C-4), 54.0 (acetal-OMe), 54.8 (acetal-OMe), 55.9 (OMe-7), 59.6
(OMe-8), 103.0 (acetal), 110.1 (C-6), 122.7 (C-5), 124.3 (C-4a), 126.8
(2C, 1-TsC-2 and TsC-6), 127.3 (2C, 4-NTsC-2 and 4-NTsC-6), 129.1
(2C, 1-NTsC-3 and 1-NTsC-5), 129.7 (2C, 4-NTsC-3 and 4-NTsC-5),
133.2 (C-8a), 137.8 (4-NTsC-1), 139.4 (1-TsC-1), 142.7 (1-TsC-4),
ArH-5 of Ts), and 7.53 (d, 2H, J¼8.5 Hz, ArH-2 and ArH-6 of Ts); 13
C
NMR (d): 21.6 (ArMe of Ts), 45.7 (C-2), 56.1 (OMe-7), 60.5 (OMe-8),
110.9 (C-6), 120.7 (C-5), 123.0 (C-4), 124.8 (C-4a), 126.1 (C-3), 127.8
(2C, TsC-2 and TsC-6), 129.0 (2C, TsC-3 and TsC-5), 137.3 (C-8a),
143.2 (2C, C-8 and TsC-1), 145.8 (TsC-4), and 152.9 (C-7); HRMS
(TOF MS ESIþion mode) calcd for
C18H19NO4SNa: 368.0933
(MþNa)þ; found: 368.0933. An increase in solvent polarity fur-
nished aldehyde 32 (8 mg, 45%).
3.11. Attempted cyclization of tosylacetal 30 with BF3$Et2O
A solution of BF3$Et2O (0.215 mL, 0.092 mmol) in dry CH2Cl2
(0.5 mL) was added dropwise to a solution of tosylacetal 30 (18 mg,
0.031 mmol) in CH2Cl2 at ꢀ40 ꢁC. After 12 h at room temperature,
the reaction was quenched with brine (5 mL) and the products
were extracted with EtOAc (4ꢂ10 mL). Drying (Na2SO4) and
143.3 (4-NTsC-4)
*
, 143.5 (C-8) , and 152.3 (C-7); HRMS (TOF MS
*
ESIþion mode) calcd for C29H36N2O8S2Na: 627.1811 (MþNa)þ;
found: 627.1813.

E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
5243
concentration of the extracts under reduced pressure, followed by
chromatography afforded 31 (6 mg, 47%) and 32 (8 mg, 48%).
(s, 3H, OMe-6), 3.20 (d, 1H, J¼13.2 Hz, H-5uf), 3.74 (s, 3H, OMe-9),
3.84 (s, 3H, OMe-8), 4.03 (ddd, 1H, J¼2.8, 5.7, 7.8 Hz, H-2df), 4.04 (d,
1H, J¼3.3 Hz, H-6), 4.07 (dd, 1H, J¼3.3, 13.2 Hz, H-5df), 4.38 (dd, 1H,
J¼5.4, 11.6 Hz, H-3a), 6.70 (s, 1H, H-7), 7.23 (d, 2H, J¼8.2 Hz, ArH-3
and ArH-5 of Ts), 7.32 (d, 2H, J¼8.3 Hz, ArH-3 and ArH-5 of Ts), 7.70
(d, 2H, J¼8.3 Hz, ArH-2 and ArH-6 of Ts), and 7.88 (d, 2H, J¼8.2 Hz,
ArH-2 and ArH-6 of Ts); 13C NMR (d): 21.5 (ArMe of Ts), 21.6 (ArMe
of Ts), 29.4 (C-3), 42.9 (C-5), 43.0 (C-2), 49.3 (C-3a), 56.2 (2C, OMe-8
and OMe-6), 60.6 (OMe-9), 74.4 (C-6), 112.2 (C-7), 126.4 (C-9b),
127.6 (2C, TsC-2 and TsC-6), 127.8 (2C, TsC-2 and TsC-6), 129.2 (2C,
TsC-3 and TsC-5), 129.6 (2C, TsC-3 and TsC-5), 130.0 (C-6a), 136.8
(TsC-1), 137.6 (TsC-1), 143.1 (2C, TsC-4 and C-9a), 143.6 (TsC-4),
146.1 (C-9), and 152.4 (C-8); HRMS (TOF MS ESIþion mode) calcd
for C28H32N2O7S2Na: 595.1549 (MþNa)þ; found: 595.1552. Further
increase in solvent polarity furnished a mixture of diastereomeric
alcohols, 33c being the most abundant one (12 mg, 9%). IR (film, n):
3482, 2924, 2852, 1598, 1496, 1337, 1266, 1158, 1056, 914, 815, 736,
3.12. Attempted cyclization of 30. Isolation of N-[7,8-
dimethoxy-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydroquinolin-
4-yl]-4-methyl-N-(2-oxoethyl)-benzenesulfonamide 32
Anhydrous ZnI2 (21 mg, 0.064 mmol) was added to sulfonami-
doacetal 30 (19 mg, 0.032 mmol) dissolved in CH2Cl2 (1 mL) and
the resulting suspension was submitted to sonication for 24 h. The
mixture was then chromatographed, furnishing aldehyde 32 (11,
mg, 54%), as an oil. IR (film, n): 2925, 1854, 1739, 1733, 1599, 1495,
1339, 1156, 816, and 672 cmꢀ1
;
1H NMR (d): 2.01 (dt, 1H, J¼6.4,
8.8 Hz, H-3uf), 2.42 (s, 3H, ArMe of Ts), 2.47 (s, 3H, ArMe of Ts), 3.21
(dt, 1H, J¼8.8, 9.0 Hz, H-3df), 3.21 (s, 3H, OMe-8), 3.36 (ddd, 1H,
J¼6.4, 8.4, 14.3 Hz, H-2uf), 3.74 (d, 2H, J¼1.4 Hz, NCH2), 3.82 (OMe-
7), 3.88 (dt, 1H, J¼9.0, 14.3 Hz, H-2df), 5.23 (dd, 1H, J¼8.4, 9.0 Hz, H-
4), 6.76 (d, 1H, J¼8.9 Hz, H-6), 7.11 (d, 1H, J¼8.9 Hz, H-5), 7.29 (d, 2H,
J¼8.4 Hz, ArH-3 and ArH-5 of Ts), 7.36 (d, 2H, J¼8.4 Hz, ArH-3 and
ArH-5 of Ts), 7.80 (d, 4H, J¼8.4 Hz, 2ꢂArH-2 and ArH-6 of Ts), and
9.47 (t, 1H, J¼1.4 Hz, CHO); 13C NMR (d): 21.5 (ArMe of Ts), 21.6
(ArMe of Ts), 28.3 (C-3), 47.2 (C-2), 53.0 (NCH2CHO), 53.7 (C-4), 55.9
(OMe-7), 59.6 (OMe-8), 110.7 (C-6), 121.8 (C-4a), 124.1 (C-5), 126.9
(2C, TsC-2 and TsC-6), 127.6 (2C, TsC-2 and TsC-6), 129.2 (2C, TsC-3
and TsC-5), 130.0 (2C, TsC-3 and TsC-5), 133.7 (C-8a), 136.6 (TsC-1),
138.9 (TsC-1), 143.1 (TsC-4), 143.6 (TsC-4), 144.2 (C-8), 152.8 (C-7),
and 197.4 (CHO); HRMS (TOF MS ESIþion mode) calcd for
and 666 cmꢀ1 1H NMR (d): 1.60–1.75 (m, 1H, H-3uf), 2.40 (s, 3H,
;
ArMe of 1-Ts), 2.45 (s, 3H, ArMe of 4-Ts), 2.64 (dddd, 1H, J¼1.6, 5.2,
10.6, 17.0 Hz, H-3df), 3.02–3.13 (m, 1H, H-2uf), 3.25 (dd, 1H, J¼1.9,
14.2 Hz, H-5uf), 3.71 (s, 3H, OMe-9), 3.85 (s, 3H, OMe-8), 4.00 (dd,
1H, J¼2.8, 14.2 Hz, H-5df), 4.02–4.13 (m, 1H, H-2df), 4.05 (dd, 1H,
J¼1.9, 2.8 Hz, H-6), 4.54 (br s, 1H, w1/2¼7.5 Hz, OH), 4.58 (dd, 1H,
J¼5.6, 11.7 Hz, H-3a), 6.81 (s, 1H, H-7), 7.29 (d, 2H, J¼8.3 Hz, ArH-3
and ArH-5 of 1-Ts), 7.34 (d, 2H, J¼8.3 Hz, ArH-3 and ArH-5 of 4-Ts),
7.75 (d, 2H, J¼8.3 Hz, ArH-2 and ArH-6 of 1-Ts), and 7.91 (d, 2H,
J¼8.3 Hz, ArH-2 and ArH-6 of 4-Ts); 13C NMR (d): 21.5 (ArMe of Ts),
21.6 (ArMe of Ts), 31.3 (C-3), 43.1 (C-2), 46.6 (C-5), 49.0 (C-3a), 56.1
(OMe-8), 60.5 (OMe-9), 66.1 (C-6), 111.6 (C-7), 125.5 (C-9a), 127.0
(C-9b), 127.5 (2C, TsC-2 and TsC-6), 127.6 (2C, TsC-2 and TsC-6),
128.7 (C-6a), 129.6 (2C, TsC-3 and TsC-5), 129.7 (2C, TsC-3 and TsC-
5), 136.8 (TsC-1), 137.6 (TsC-1), 143.7 (2C, 2ꢂTsC-4), 146.1 (C-9), and
152.8 (C-8); HRMS (TOF MS ESIþion mode) calcd for C27H31N2O7S2:
559.1573 (Mþ1)þ; found: 559.1578.
C
27H31N2O7S2: 559.1573 (Mþ1)þ; found: 559.1578.
3.13. SnCl4-mediated cyclization of tosylacetal 30
To a solution of tosylacetal 30 (121 mg, 0.20 mmol) in CH2Cl2
(10 mL) cooled to ꢀ78 ꢁC, was added dropwise a CH2Cl2 solution of
SnCl4 (0.54 mL, 0.40 mmol). After 1.5 h at ꢀ78 ꢁC, the reaction
temperature was increased to ꢀ60 ꢁC and left overnight. The sys-
tem was slowly heated up to room temperature and 0.2 mL of
MeOH was added to quench the Lewis acid. After 10 min of stirring,
brine (5 mL) was added and the organic products were extracted
with EtOAc (4ꢂ20 mL). The organic extracts were combined, suc-
cessively washed with saturated NaHCO3 (5 mL) and brine (5 mL),
dried over Na2SO4, concentrated under reduced pressure, and
chromatographed, furnishing 1,2-dihydroquinoline derivative 31
(16 mg, 23%), aldehyde 32 (5 mg, 4%), followed by 33a (10 mg, 9%).
IR (film, n): 2954, 2923, 2853, 1598, 1494, 1341, 1158, and
3.14. SnCl4-mediated cyclization of nosylacetal 34
To a solution of nosylacetal 34 (28 mg, 0.04 mmol) in CH2Cl2
(1.6 mL) cooled to ꢀ78 ꢁC, was added dropwise a CH2Cl2 solution of
SnCl4 (0.155 mL, 0.128 mmol). After 1.5 h at ꢀ78 ꢁC, the reaction
temperature was increased to ꢀ60 ꢁC and left overnight. The sys-
tem was slowly heated up to room temperature and 0.2 mL of
MeOH was added to quench the Lewis acid. After 10 min of stirring,
brine (5 mL) was added and the organic products were extracted
with EtOAc (4ꢂ20 mL). The organic extracts were combined, suc-
cessively washed with saturated NaHCO3 (5 mL) and brine (5 mL),
dried over Na2SO4, concentrated under reduced pressure, and
chromatographed, furnishing 35a (4.7 mg, 18%), as an oil. 1H NMR
(d): 1.70–1.84 (m, 1H, H-3uf), 2.45 (s, 3H, ArMe of Ts), 2.71 (dddd,
1H, J¼5.7, 6.3, 10.0, 11.4 Hz, H-3df), 2.98 (dd, 1H, J¼9.8, 13.5 Hz, H-
5uf), 3.04 (ddd, 1H, J¼5.7, 9.4, 13.9 Hz, H-2uf), 3.55 (s, 3H, OMe-6),
3.66 (s, 3H, OMe-9), 3.84 (s, 3H, OMe-8), 3.91 (dd, 1H, J¼4.7, 9.8 Hz,
H-6), 4.06 (ddd, 1H, J¼6.1, 10.0, 13.9 Hz, H-2df), 4.25 (dd, 1H, J¼4.7,
13.5 Hz, H-5df), 4.69 (dd, 1H, J¼6.0, 11.4 Hz, H-3a), 6.94 (s, 1H, H-7),
7.35 (d, 2H, J¼8.4 Hz, ArH-3 and ArH-5 of Ts), 7.94 (d, 2H, J¼8.4 Hz,
ArH-2 and ArH-6 of Ts), 8.04 (d, 2H, J¼9.0 Hz, ArH-2 and ArH-6 of
Ns), and 8.35 (d, 2H, J¼9.0 Hz, ArH-3 and ArH-5 of Ns); HRMS (TOF
MS ESIþion mode) calcd for C27H30N3O9S2: 604.1424 (Mþ1)þ;
found: 604.1404. This was followed by 35b (4.7 mg, 18%), as an oil.
1H NMR (d): 1.82 (dddd, 1H, J¼5.9, 6.7, 9.7, 12.6 Hz, H-3uf), 2.45 (s,
3H, ArMe of Ts), 2.84 (m, 1H, H-3df), 3.05 (s, 3H, OMe-6), 3.06 (ddd,
1H, J¼3.9, 9.7, 13.2 Hz, H-2uf), 3.23 (dd, 1H, J¼1.7, 14.8 Hz, H-5uf),
3.74 (s, 3H, OMe-9), 3.84 (s, 3H, OMe-8), 4.02 (dd, 1H, J¼1.7, 2.4 Hz,
H-6), 4.07 (ddd, 1H, J¼6.7, 7.1, 13.2 Hz, H-2df), 4.31 (dd, 1H, J¼2.4,
14.8 Hz, H-5df), 4.68 (dd, 1H, J¼5.9, 11.7 Hz, H-3a), 6.64 (s, 1H, H-7),
7.35 (d, 2H, J¼8.4 Hz, ArH-3 and ArH-5 of Ts), 7.96 (d, 2H, J¼8.4 Hz,
1092 cmꢀ1
;
1H NMR (d): 1.73 (dddd, 1H, J¼6.0, 6.2, 9.9, 11.0 Hz, H-
3uf), 2.41 (s, 3H, ArMe of 1-Ts), 2.44 (s, 3H, ArMe of 4-Ts), 2.63–2.76
(m, 1H, H-3df), 2.89 (dd, 1H, J¼9.8, 13.3 Hz, H-5uf), 3.08 (ddd, 1H,
J¼4.1, 9.9, 13.2 Hz, H-2uf), 3.50 (s, 3H, OMe-6), 3.68 (s, 3H, OMe-9),
3.83 (dd, 1H, J¼4.8, 9.8 Hz, H-5df), 3.84 (s, 3H, OMe-8), 4.07 (ddd,
1H, J¼2.9, 6.2,13.2 Hz, H-2df), 4.13 (dd,1H, J¼4.8,13.3 Hz, H-6), 4.50
(dd, 1H, J¼6.0, 11.5 Hz, H-3a), 6.93 (s, 1H, H-7), 7.29 (d, 2H, J¼8.2 Hz,
ArH-3 and ArH-5 of Ts), 7.34 (d, 2H, J¼8.3 Hz, ArH-3 and ArH-5 of
Ts), 7.69 (d, 2H, J¼8.3 Hz, ArH-2 and ArH-6 of Ts), and 7.91 (d, 2H,
J¼8.2 Hz, ArH-2 and ArH-6 of Ts); 13C NMR (d): 21.5 (ArMe of Ts),
21.6 (ArMe of Ts), 29.4 (C-3), 42.8 (C-5), 43.0 (C-2), 49.5 (C-3a), 56.0
(OMe-8), 57.5 (OMe-6), 60.4 (OMe-9), 73.0 (C-6), 107.9 (C-7), 124.7
(C-9a), 126.9 (2C, TsC-2 and TsC-6), 127.6 (2C, TsC-2 and TsC-6),
129.6 (2C, TsC-3 and TsC-5), 129.9 (2C, TsC-3 and TsC-5), 130.0 (C-
9b)
*
, 130.3 (C-6a) , 137.4 (TsC-1), 137.7 (TsC-1), 143.6 (TsC-4), 143.7
*
(TsC-4), 145.2 (C-9), and 152.6 (C-8); HRMS (TOF MS ESIþion mode)
calcd for C28H32N2O7S2Na: 595.1549 (MþNa)þ; found: 595.1554.
Increasing solvent polarity afforded 33b (28 mg, 24%), as an oil. IR
(film, n): 2954, 2924, 2853, 1598, 1496, 1337, 1157, and 1092 cmꢀ1
;
1H NMR (d): 1.71 (dddd, 1H, J¼5.4, 8.0, 9.6, 11.9 Hz, H-3uf), 2.39 (s,
3H, ArMe of 1-Ts), 2.43 (s, 3H, ArMe of 4-Ts), 2.75 (dddd, 1H, J¼2.8,
3.5,11.6,11.9 Hz, H-3df), 3.13 (ddd,1H, J¼3.5, 7.8, 9.6 Hz, H-2uf), 3.13

5244
E.L. Larghi et al. / Tetrahedron 64 (2008) 5236–5245
ArH-2 and ArH-6 of Ts), 8.04 (d, 2H, J¼8.8 Hz, ArH-2 and ArH-6 of
Ns), and 8.27 (d, 2H, J¼8.8 Hz, ArH-3 and ArH-5 of Ns); 13C NMR (d):
21.6 (ArMe of Ts), 32.5 (C-3), 42.8 (C-5), 43.9 (C-2), 49.3 (C-3a), 55.9
(OMe-8), 56.2 (OMe-6), 60.6 (OMe-9), 74.2 (C-6), 112.7 (C-7), 123.5
H-5df), 3.74 (s, 3H, OMe-9), 3.79 (s, 3H, OMe-8), 4.24 (dd, 1H, J¼4.4,
11.8 Hz, H-3a), 4.43 (br s, 1H, w1/2¼36 Hz, NH-1), 5.8–7.5 (br s, 1H,
NH-4), and 6.00 (s, 1H, H-7); 13C NMR (d): 25.3 (C-6), 25.5 (C-3),
39.5 (C-2), 42.1 (C-5), 51.4 (C-3a), 55.7 (OMe-8), 59.9 (OMe-9),100.0
(C-7), 106.2 (C-9b), 126.5 (C-6a), 132.3 (C-9), 137.3 (C-9a), and 152.5
(C-8); HRMS (TOF MS ESIþion mode) calcd for C13H19N2O2:
235.1447 (Mþ1)þ; found: 235.1445.
(2C, NsC-3 and NsC-5), 125.6 (C-9a)
*
, 125.9 (C-9b) , 127.8 (2C, TsC-2
*
and TsC-6), 129.2 (2C, NsC-2 and NsC-6), 129.6 (2C, TsC-3 and TsC-
5), 130.0 (C-6a), 137.4 (TsC-1), 143.8 (TsC-4), 145.6 (C-9), 146.5 (NsC-
1), 149.8 (NsC-4), and 152.4 (C-8); HRMS (TOF MS ESIþion mode)
calcd for C27H30N3O9S2: 604.1424 (Mþ1)þ; found: 604.1409. In-
creasing solvent polarity furnished 35c (4 mg, 16%), as an oil. 1H
NMR (d): 1.55 (br s, 1H, OH), 1.83 (dddd, 1H, J¼6.4, 7.0, 9.6, 11.0 Hz,
H-3uf), 2.46 (s, 3H, ArMe of Ts), 2.76 (dddd, 1H, J¼6.1, 6.3, 11.0,
11.5 Hz, H-3df), 3.04 (ddd, 1H, J¼6.1, 9.6, 14.0 Hz, H-2uf), 3.36 (dd,
1H, J¼10.1, 14.0 Hz, H-5uf), 3.69 (s, 3H, OMe-9), 3.85 (s, 3H, OMe-8),
4.07 (ddd, 1H, J¼6.3, 7.0, 14.0 Hz, H-2df), 4.29 (dd, 1H, J¼4.1, 14.0 Hz,
H-5df), 4.67 (dd, 1H, J¼4.1, 10.1 Hz, H-6), 4.76 (dd, 1H, J¼6.4, 11.5 Hz,
H-3a), 7.02 (s, 1H, H-7), 7.35 (d, 2H, J¼8.4 Hz, ArH-3 and ArH-5 of
Ts), 7.95 (d, 2H, J¼8.4 Hz, ArH-2 and ArH-6 of Ts), 8.05 (d, 2H,
J¼8.8 Hz, ArH-2 and ArH-6 of Ns), and 8.35 (d, 2H, J¼8.8 Hz, ArH-3
and ArH-5 of Ns); 13C NMR (d): 21.6 (ArMe of Ts), 32.2 (C-3), 43.0 (C-
5), 47.0 (C-2), 49.6 (C-3a), 54.0 (C-6), 56.2 (OMe-8), 60.6 (OMe-9),
Acknowledgements
The authors gratefully thank UNR, CONICET (PIP No. 5439), and
ANPCyT (PICT Nos. 06-12532 and 06-38165) for financial support.
E.L.L. thanks CONICET for his fellowship. Ms. Annabelle Gillig (EPFL,
Switzerland) is acknowledged for carrying out the high-resolution
mass spectral analyses.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.03.036.
111.4 (C-7), 124.0 (2C, NsC-3 and NsC-5), 125.3 (C-9a)
*
, 126.3 (C-
9b) , 127.8 (2C, TsC-2 and TsC-6), 129.3 (2C, NsC-2 and NsC-6), 129.7
*
References and notes
(2C, TsC-3 and TsC-5), 129.9 (C-6a), 137.3 (TsC-1), 143.9 (TsC-4),
145.1 (C-9), 146.8 (NsC-1), 150.1 (NsC-4), and 153.1 (C-8); HRMS
(TOF MS ESIþion mode) calcd for C26H28N3O9S2: 590.1267; found:
590.1244. This was followed by 35d (5.6 mg, 22%), as an oil. 1H NMR
(d): 1.57 (br s, 1H, OH), 1.79 (dddd, 1H, J¼6.1, 7.0, 9.2, 12.0 Hz, H-3uf),
2.46 (s, 3H, ArMe of Ts), 2.71–2.83 (m, 1H, H-3df), 3.04 (ddd, 1H,
J¼5.7, 7.0, 13.8 Hz, H-2uf), 3.29 (dd, 1H, J¼1.6, 14.6 Hz, H-5uf), 3.72
(s, 3H, OMe-9), 3.84 (s, 3H, OMe-8), 4.05 (ddd, 1H, J¼6.0, 6.1,
13.8 Hz, H-2df), 4.22 (dd, 1H, J¼2.2, 14.6 Hz, H-5df), 4.60 (dd, 1H,
J¼1.6, 2.2 Hz, H-6), 4.77 (dd, 1H, J¼6.1, 11.6 Hz, H-3a), 6.76 (s, 1H, H-
7), 7.36 (d, 2H, J¼8.6 Hz, ArH-3 and ArH-5 of Ts), 7.97 (d, 2H,
J¼8.6 Hz, ArH-2 and ArH-6 of Ts), 8.10 (d, 2H, J¼8.8 Hz, ArH-2 and
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ArH-6 of Ns), and 8.31 (d, 2H, J¼8.8 Hz, ArH-3 and ArH-5 of Ns); 13
C
NMR (d): 21.6 (ArMe of Ts), 31.9 (C-3), 42.9 (C-2), 46.5 (C-5), 49.2 (C-
3a), 55.1 (OMe-8), 60.5 (OMe-9), 66.0 (C-6), 111.7 (C-7), 124.0 (2C,
NsC-3 and NsC-5), 125.2 (C-9a)
*
, 127.8 (2C, TsC-2 and TsC-6), 128.1
(C-9b) , 129.1 (2C, NsC-2 and NsC-6), 129.6 (2C, TsC-3 and TsC-5),
*
130.1 (C-6a), 136.4 (TsC-1), 143.9 (TsC-4), 145.5 (C-9), 146.3 (NsC-1),
150.0 (NsC-4), and 153.0 (C-8); HRMS (TOF MS ESIþion mode) calcd
for C26H27N3NaO9S2: 612.1086; found: 612.1089.
3.15. 8,9-Dimethoxy-2,3,3a,4,5,6-hexahydro-1H-benzo[de]-
[1,6]naphthyridine (2,3,3a,4,5,6-hexahydroaaptamine) 18
A solution of 33a and 33b (38 mg, 0.066 mmol) in anhydrous
THF (1.5 mL) was added via cannula to freshly condensed, refluxing
(ꢀ33 ꢁC) ammonia. Metallic sodium was melted under toluene and
aspired into a 0.2 mL pipette, where it solidified as a thin wire.29
The thus prepared sodium wire was carefully placed in contact with
the reaction mixture, where a blue-greenish color developed. The
sodium wire was introduced each time the color fainted, and this
operation was repeated until a deep blue color was observed, which
persisted for 5 min, when the remaining wire was finally removed.
The reaction was quenched by addition of solid NH4Cl (z100 mg).
The ammonia was left to evaporate and the remaining reaction
products were admixed with silica gel and chromatographed, fur-
nishing 18 (13 mg, 83%), as a solid, mp 105–107 ꢁC (hexane; lit.16a
106–108 ꢁC). IR (KBr, n): 3403, 3250, 2956, 2865, 2510, 1610, 1516,
1464, 1324, 1239, 1155, 1010, and 685 cmꢀ1; 1H NMR (d): 2.13 (ddd,
1H, J¼3.9, 11.8, 23.9 Hz, H-3uf), 2.50–2.60 (m, 1H, H-3df), 2.81 (br
dd, 1H, J¼11.1, 20.8 Hz, H-6uf), 3.22 (dd, 1H, J¼3.6, 11.1 Hz, H-6df),
3.30 (br dd, 1H, J¼3.6, 20.8 Hz, H-5uf), 3.40 (dt, 1H, J¼3.9, 12.3 Hz,
H-2uf), 3.45–3.55 (m, 1H, H-2df), 3.65 (dd, 1H, J¼11.1, 20.8 Hz,
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