Cyclization reactions of N-acryloyl-2-aminobenzaldehyde derivatives: formal total synthesis of martinellic acid

Article abstract of DOI:10.1016/j.tet.2006.06.104

N-Alkyl acryloylamides derived from o-aminobenzaldehyde derivatives react with N-alkyl glycine derivatives to provide cis-fused pyrrole[3,2-c]quinolones in moderate yield and high diastereoselectivity. These same substrates engage in a tandem Michael-Mann

Full text of DOI:10.1016/j.tet.2006.06.104

Tetrahedron 62 (2006) 8755–8769
Cyclization reactions of N-acryloyl-2-aminobenzaldehyde
derivatives: formal total synthesis of martinellic acid
*
Yong He, Hossen Mahmud, Remond Moningka, Carl J. Lovely and H. V. Rasika Dias
*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States
Received 24 April 2006; revised 26 June 2006; accepted 29 June 2006
Available online 24 July 2006
Abstract—N-Alkyl acryloylamides derived from o-aminobenzaldehyde derivatives react with N-alkyl glycine derivatives to provide
cis-fused pyrrole[3,2-c]quinolones in moderate yield and high diastereoselectivity. These same substrates engage in a tandem Michael–
Mannich pathway on treatment with a secondary amine, providing corresponding quinolone derivatives. The elaboration of a pyrroloquinolone
derivative via addition of an in situ generated functionalized copper acetylide to an in situ generated iminium ion provided the C2-substituted
derivative. Global deprotection and reduction of the alkyne afford the tricyclic triamine core (as the HCl salt) found in martinellic acid.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
NH
The Martinella alkaloids, martinelline (1) and martinellic
acid (2), were isolated from the South American medicinal
plant Martinella iquitosensis by Witherup and co-workers
at Merck Laboratories in 1995 in the course of a natural prod-
ucts screening program.1,2 These alkaloids were among the
first potent, naturally occurring (non-peptide) bradykinin
(BK) receptor antagonists to be reported.3 In addition to their
biological activity, these alkaloids contain a partially reduced
pyrrolo[3,2-c]quinoline ring system, which had not been
observed in a natural product prior to the isolation of 1 and 2,
although the parent aromatic heterocycle was well known.2
The novelty of the ring system found in martinelline and mar-
tinellic acid combined with the BK antagonistic behavior of
these two natural products has elicited significant interest
from the synthetic community,2,4–17 which in turn has led
to the development of a number of strategies for the assembly
of the heterocyclic core and most recently to several total
syntheses of 1 and 2.7,10,14,16,17 Our approach to these targets,
which is illustrated below in a retrosynthetic manner (Fig. 1),
involves the obvious disconnection of the guanidine groups
and functional group manipulations to provide the tricyclic
core 3. Further, disconnection of the C2–C10 bond then pro-
vides the key tricyclic intermediate 4 as shown in Figure 1,
which not only should function as an useful intermediate
en route to the natural products, but also may be useful for
the eventual preparation of a diverse library of analogs for ap-
plication in chemical biology studies. It was envisioned that
HN
7
Guanylation
N
5
Guanylation
RO2C
H
N
H
N
2
Carbonylation
N
H
NH
H
N
NH2
NH
1: Martinelline, R =
2: Martinellic acid, R = H
Ph
[3+2]
N
HN
N
Br
Br
N
O
PG
Iminium ion/
Allylsilane
PG
4
3
Ph
−
+
N
Br
Br
CO2Me
NH2
N
H
O
5
6
Figure 1. Retrosynthetic analysis of 1 and 2.
the carbonyl group in the C2-position could be utilized for
the stereoselective incorporation of the three-carbon side
chain found in the natural products, presumably by the Lewis
* Corresponding authors. Tel.: +1 817 272 5446; fax: +1 817 272 3808
(C.J.L.); tel.: +1 817 272 3813 (H.V.R.D.); e-mail addresses: lovely@
uta.edu; dias@uta.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.104

8756
Y. He et al. / Tetrahedron 62 (2006) 8755–8769
acid-mediated nucleophilic addition of an allylsilane to an
iminium ion. The pyrroloquinolone core 4 would be accessed
in turn via an intramolecular [3+2] cycloaddition reaction
between a non-stabilized azomethine ylide and an electron
deficient alkene (Fig. 1, 5/4).18,19 Related azomethine
ylide-based strategies for construction of the key pyrrolo-
[3,2-c]quinoline skeleton have not only been investigated
by our group,9 but also by Snider et al.10 and by Nyerges
et al. (intermolecular variant with stabilized ylides).13
(0.3 mmol scale, 88%; 8.0 mmol scale, 55%). PCC oxida-
tion only afforded the product in a moderate 40% yield.
Ultimately, the hypervalent IBX (o-iodoxybenzoic acid)
reagent27 was found to give the most satisfactory result pro-
viding 13 in an excellent yield, regardless of the reaction
scale.
O
CH2OH
a
b
O
91%
95%
NH
Me
N
Me
O
Herein, we report the full details of our investigation of the
azomethine ylide cycloaddition reactions of the N-acryloyl-
2-aminobenzaldehyde derivatives for the construction of
pyrroloquinolones 4, and subsequent conversion of one of
these cycloadducts into an advanced precursor for the total
synthesis of the Martinella alkaloids.9 In addition to the
formal total synthesis, the observation of some initially
unanticipated, but nonetheless interesting, events during the
course of the reactions of N-acryloyl-2-aminobenzaldehyde
substrates with N-alkyl glycine derivatives, i.e., a domino
Michael–Mannich reaction, are described.
10
11
CH2OH
O
N
CHO
c
d
O
80%
N
Me
Me
13
12
R
N
5a
14a: R = Bn (66%+5% trans)
14b: R = Me (58%)
2a
14c: R = PMB (44%+5% trans)
N
Me
O
Our initial approach to the construction of the key heterocy-
clic core of these natural products involved the reaction of
acrylamide derivative 7 with various N-alkyl glycine deriva-
tives.20,21 However, the expected product 8 was not obtained,
but adducts 9a–c were obtained from a net decarboxylative
Michael addition (Scheme 1).22 Extensive control studies
indicated that the requisite azomethine ylide 5 (Fig. 1) was
being formed, but underwent protonation and hydrolysis,
leading to formation of the amine, followed by conjugate
addition to the acryloyl moiety. Our interpretation of this
observation centered on low population of the reactive
rotamer.23,24 Therefore to address this possibility, we turned
our attention to the use of N-alkyl acrylamide derivatives.25
Scheme 2. Reagents and conditions: (a) LiAlH4, THF; (b) acryloyl chloride,
CH2Cl2, NaHCO3; (c) IBX, DMSO; (d) RNHCH2CO2H$HCl, Et3N,
toluene, reflux.
When 13 was subjected to reaction with N-benzylgly-
cine$HCl in refluxing toluene, we were delighted to find
that it had undergone the desired cycloaddition reaction to
provide the cis-fused pyrroloquinolone 14a in 66% yield.
In addition to the cis-fused adduct (J2a,5a¼5.5 Hz), a small
quantity of the trans-adduct (J2a,5a¼13.8 Hz) ca. 5% was iso-
lated.9c In similar cycloaddition reactions with sarcosine and
PMB-glycine$HCl, cis-pyrroloquinolones, 14b and 14c
were obtained in 58 and 44% (the latter in DMF, vide infra)
yields, respectively. The corresponding trans-isomers were
also produced in these reactions, but in less than 5% yield
R
N
Br
X
1
N
H
O
based on the analysis of the H NMR spectra of the crude
reaction mixture. However, isolation of this minor adduct
only proved possible with the N-PMB-protected derivative.
O
a
Br
8
N
H
O
O
It was observed in initial experiments conducted with 13 and
PMB-glycine$HCl that the expected cycloaddition product
14c was isolated in relatively poor yield (<20%, Scheme 3).
This outcome struck us as unusual as our prior experience
suggested that this protected glycine derivative should be-
have similarly to the benzyl analog. It was determined that
this was due to the formation of two byproducts 15c and
16c, while similar reactions with sarcosine or benzylgly-
cine$HCl appear to afford only the cycloaddition products
in reasonable yields. Analysis of the NMR data suggested
that the structure of byproduct 15c was a 1,2,3,4-tetrahydro-
quinolin-2-one derivative, with trans-substituents at C3 and
C4 (J3,4¼12.4 Hz), and byproduct 16c was established to
be the 1,2-dihydroquinolin-2-one derivative. The initial cy-
cloaddition reaction with PMB-glycine$HCl was performed
in toluene at reflux for 10 h, giving 14c (16%), 15c (11%),
and 16c (20%) (entry 1, Table 1). It was subsequently deter-
mined that these experiments were conducted with an older
sample of N-PMB-glycine$HCl, which presumably had
picked up water from the atmosphere. Employing more
Br
7
O
R
N
H
N
Me
9a: R = Bn, 68%
9b: R = Me, 76%
9c: R = PMB, 50%
Scheme 1. Reagents and conditions: (a) RNHCH2CO2H (R¼Bn, PMB as
HCl salt), Et3N, DMF, reflux.
Initially attempts were made to alkylate 7 with MeI directly,
however, these experiments were unsuccessful, and there-
fore, N-methyl isatoic anhydride (10) was employed as the
starting material. Reduction with LiAlH4 provided the
known amino alcohol 11, which was then acylated chemo-
selectively with acryloyl chloride according to the protocol
of Heaney and co-workers,26 providing 12 in an excellent
yield (Scheme 2). Subsequent MnO2 oxidation provided
the required cyclization precursor, acrylamide 13, however,
the yield of this reaction was found to be scale dependent

Y. He et al. / Tetrahedron 62 (2006) 8755–8769
8757
recently prepared material led to an improvement in the
amount of 14c produced, but byproducts 15c and 16c were
still obtained in reasonable amounts (entry 2, Table 1). Inter-
estingly, extending the reaction time to 20 h saw a reduction
in the amount of 15c formed, providing only 14c and 16c,
whereas, adding water to the reaction increased the yield of
byproduct 15c. In contrast, when the reaction was carried
out in DMF at reflux for 1 h, only byproduct 15c was
obtained, along with the expected cycloadduct 14c.
the sterically more favorable pseudoequatorial position in
the putative transition state 18 (Scheme 4). It has also been
demonstrated in the studies described above that the PMB
methylamine is formed under these reaction conditions.
Thus, when PMB methylamine functions as the nucleophile,
19 and/or 20 would be formed,29 elimination then affords the
more stable conjugated 1,2-dihydroquinolin-2-one 16c.14b,30
The time variation in byproduct distribution suggests that
15c is the kinetic product and 16c is the thermodynamic
product. It is assumed that the initial concentration of H2O
in the reaction mixture would be higher than NHMePMB
as the formation of the latter nucleophile requires additional
steps, and thus an induction period for the concentration to
build up. However, once it accumulates it competes effec-
tively with H2O leading to the formation of 16c, which is
thermodynamically more stable due to its extended conjuga-
tion. This is consistent with the experimental observation
that extending the reaction time leads to the exclusive forma-
tion of 16c. The isolation of these byproducts in the case of
reactions involving an N-PMB moiety and not with an N-Bn
or N-Me warrants further discussion. Several factors may
contribute to the competitive formation of the byproducts
and the desired pyrroloquinolone. (a) The PMB moiety is
electron donating; therefore, the azomethine ylide is ren-
dered more electron rich and as a result is rapidly protonated
(Scheme 4, 17/18), and thus cannot participate in cyclo-
addition. (b) The thus produced iminium ion is more electron
rich and thus is less susceptible to hydrolysis, therefore, it
accumulates and will lead to an increase in intermolecular
reactions (with water or amine). (c) p-Methoxybenzyl-
methylamine is more nucleophilic than methylbenzylamine
and dimethylamine, leading to an increase in the rate of
Michael addition processes.31
PMB
PMB
NMe OH
NMe
O
CO2H·HCl
PMBHN
+
14c
+
13
NEt3, solvent,
reflux
N
O
N
Me
16c
Me
15c
Scheme 3.
Table 1. Product distribution from reaction of PMB-glycine with aldehyde
13
Entry
Solvent
Time (h)
14c (%)
15c (%)
16c (%)
1
2
3
4
Toluene
Toluene
Toluene
DMF
10
8
20
1
16
38
40
44
11
20
0
20
18
48
0
10
Our interpretation of the results obtained in these reactions
involves two competing pathways, the ‘normal’ [3+2]
pathway (17/14c) and a domino Michael–Mannich reac-
tion sequence (17/15c and 16c) and are illustrated in
Scheme 4.28 The studies on the decarboxylative Michael
addition described previously (Scheme 9)9c have already
shown that the azomethine ylide can be protonated under
the reaction conditions to form an iminium ion 18. In the
presence of nucleophiles (H2O or MeNHR), 18 undergoes
an intermolecular Michael reaction and subsequent intramo-
lecular Mannich reaction to furnish the cycloadduct 1,2,3,4-
tetrahydroquinolin-2-one derivatives 15c or 16c, the latter
after an elimination reaction. The cycloaddition appears to be
stereoselective, providing the trans-substituted product, pre-
sumably as a result of the large iminium moiety occupying
In order to provide support for the proposed mechanism,
some additional experiments were performed. For example,
aldehyde 13 was heated at reflux with NHMeBn in the pres-
ence of Et3N under various conditions, the results of which
are listed in Table 2 (Scheme 5). As can be seen, in refluxing
toluene, both analogs 15a and 16a were obtained in 38 and
13%, respectively. Adding water to the reaction mixture
led to the formation of 15a in an excellent 85% yield plus
a small amount (12%) of 16a. In refluxing DMF and
−
PMB
NMe
+
PMB
N
Nu
Nu: =
H2O
+
OH
H
[3+2]
B
H
N
14c
Me
PMB
fast
Michael then
intramolecular
Mannich
N
O
N
Me
15c
O
N
Me
O
+
Me
18
17
Nu: =
kinetic product
Michael then
intramolecular
Mannich
MeNHPMB
PMB
X
H
PMB
+
X
N Me
NMe
O
+
Nu: =
B
H
- HX
NMe
PMB
MeNHPMB
13
slow
N
O
N
Me
16c
N
Me
O
Michael then
Me
intramolecular
aldol
19: X = NPMBMe
20: X = OH
21: X = NPMBMe
22: X = OH
thermodynamic product
Scheme 4.

8758
Y. He et al. / Tetrahedron 62 (2006) 8755–8769
Table 2. Yields and conditions for the Michael–Mannich reaction of 13
Br
CH2OH
Br
CO2Me
NH2
a, b
90%
c
Entry
Solvent
Time (h)
15a (%)
16a (%)
89%
NH
Bn
1
2
3
4
5
6
Toluene
Toluene, H2O (5 equiv)
DMF
DMF
DMF
DMF, H2O
3
2
1.5
2
8
1.5
38
85
70
60
0
13
12
28
38
90
0
6
23
Br
CHO
O
N
Br
CH2OH
O
N
90
d
e
90%
Bn
Bn
extending the reaction time led to the formation of more of
the thermodynamic product 16a and less of the kinetic prod-
uct 15a. Heating at reflux in DMF for 8 h led to the exclusive
formation of 16a in an excellent 90% yield. Not surprisingly,
adding water to the reaction and heating at reflux for a short
time (1.5 h) gave the 15a exclusively. These results provide
compelling evidence that compound 15a is the kinetic prod-
uct and 16a is formed as the thermodynamic product. This
was further supported by control experiments in which 15a
was heated at reflux with only Et3N, no reaction was
observed but when NHMeBn was added, 15a converted to
16a quantitatively after refluxing for 18 h. Thus by control-
ling the reaction conditions, either cycloadduct (15a or 16a)
can be obtained in an excellent yield. The fact that MeNHBn
participates in the tandem Mannich–Michael sequence
strongly suggests that the corresponding azomethine ylide
undergoes cycloaddition faster than protonation.
24
25
Bn
Bn
Bn
NMe
O
N
N
5a
Br
+
Br
Br
2a
+
N
N
O
N
O
Bn
27 (16%)
Bn
cis-26 (51%)
Bn
trans-26 (7%)
86%
Bn
f
H
N
N
MeO2C
MeO2C
g
95%
N
O
N
O
Bn
Bn
Bn
Bn
28
29
NMe
NMe
O
OH
O
Scheme 6. Reagents and conditions: (a) BzCl, NaHCO3, CH2Cl2, 0 ꢀC/rt;
(b) LiAlH4, THF, ꢁ9 ꢀC/ rt; (c) acryloyl chloride, NaHCO3, CH2Cl2; (d)
IBX, DMSO; (e) BnNHCH2CO2H$HCl, PhMe, Et3N, reflux; (f) Pd(OAc)2,
PPh3, CO (60 psi), MeOH, i-Pr2NEt, DMF, 100 ꢀC; (g) 20% Pd(OH)2/C,
HCl, H2, MeOH.
BnNHMe
13
+
NEt3, solvent,
reflux
N
CH3
N
CH3
15a
16a
BnNHMe
on this adduct (Fig. 2), which unequivocally demonstrated
the cis fusion of the pyrrole/quinolone ring system. In addi-
tion to the major cis-adduct, a small quantity (7%) of the dia-
stereoisomer, trans-26 (J2a,5a¼13.8 Hz) was isolated.9 This
stereochemical assignment was confirmed independently
NEt3, solvent,
reflux
Scheme 5.
Although the N-methyl derivatives were useful for assessing
the influence of N-substituents in the azomethine ylide cyclo-
addition reaction, as far as the total synthesis was concerned,
a more appropriate substrate had to be evaluated which
contained, inter alia, a readily removable N1-protecting
group and a halo moiety at C7 for introduction of the carboxyl
group. Thus, the N-benzyl acrylamide derivative 25 was
identified as being appropriate and was constructed through
a largely analogous sequence of reactions to those previously
employed for the synthesis of 13. Thus, benzoylation of
anthranilate derivative 632 and reduction with LiAlH4 gave
the N-benzyl alcohol 23 (Scheme 6). Subsequent acroylation
and IBX-oxidation afforded the cyclization substrate 25.
Gratifyingly, when 25 was subjected to the cycloaddition re-
action using N-benzylglycine in toluene at reflux, the desired
pyrroloquinolone, cis-26 was obtained in 51% yield
(Scheme 6). The H5a benzylic proton appeared as a doublet
in the 1H NMR spectrum at d¼3.40 ppm, with an associated
coupling constant of 5.0 Hz, which suggested that the ring
fusion was cis (the magnitude of the J-value is consistent
with our previous results).9 This assignment was subse-
quently confirmed through an X-ray structure determination
Figure 2. X-ray structure of cis-26 (bridge head hydrogens picked out for
emphasis).

Y. He et al. / Tetrahedron 62 (2006) 8755–8769
8759
benzyl protecting groups, interestingly with Pearlman’s cat-
alyst, the N5-benzyl group was removed chemoselectively
to provide a polar product, 29, in 95% (Scheme 6). At this
point, no further attempts were made to remove the
quinolinoyl benzyl group, or to find conditions to remove
both simultaneously, rather we moved onto developing
approaches for the incorporation of the C2-substitutent.
As described above, it was our intent to incorporate the
C2-substituent via the formation of the iminium ion, and
subsequently trap it through reaction with a nucleophilic
C3-synthon. Although the formation of N-acyliminium
(and other electron withdrawing groups on nitrogen) ions
is well precedented,33 the generation and trapping of imi-
nium ions from simple N-alkyl lactams, are much less
common. Overman et al. have demonstrated that reduction
of an N-benzyl lactam to the a-hydroxybenzylamine using
DIBAL as the reducing agent, followed by acid catalyzed
elimination, will provide the corresponding N-benzyl imi-
nium ion salt,34 which exhibits very good diastereoselec-
tivity in the nucleophilic addition reaction of Grignard
reagents. Attempts to employ similar procedures with cis-
26, involving the preparation of iminium salt and subsequent
nucleophilic addition of allylmagnesium bromide were un-
successful. Given this failure, we decided to investigate the
preparation and utility of the corresponding a-methoxy-
amine as an iminium ion precursor. Accordingly, the N-ben-
zyl aminol 31 was prepared by reduction of cis-26 using
DIBAL at ꢁ78 ꢀC providing a 1:0.15 mixture of two diaste-
reomers (for the major isomer, J2,2a¼3.2 Hz) (Scheme 7).35
Without further purification, the mixture was converted to
the corresponding a-methoxyamine 32 in 98% yield as a
single diastereomer (J2,2a¼1.8 Hz) by simply refluxing in
CHCl3/MeOH. Compound 32 was then treated with allyl-
trimethylsilane in the presence of a Lewis acid, TiCl4. The
putative iminium ion intermediate 33, generated in situ
underwent nucleophilic addition at C2, presumably from the
Figure 3. X-ray structure of trans-26 (bridge head hydrogens picked out for
emphasis).
through X-ray crystallography (Fig. 3). The formation of the
cis/trans-isomers appears to be under kinetic control, since
subjection of either isomer to the reaction conditions did
not result in their interconversion. In addition to cis-26 and
trans-26, 16% of a polar byproduct was also isolated. The
structure of compound was assigned as 27 and this is based
on the NMR data, which is similar to 16a, and presumably
arises through a similar pathway to the formation of 16b
in the course of the cycloaddition reactions with PMB-
protected glycine. Interestingly, however, the trans-disubsti-
tuted analog of 15a was not observed in these reactions.
With cis-26 in hand, methods for the introduction of the
C7-carboxyl group were evaluated. In our earlier studies,
Pd-catalyzed carbonylations were employed, and thus we
gravitated toward these protocols.9 However, unlike the
carbonylation reaction (conditions¼Pd(OAc)2, PPh3, CO,
NaOAc) employed previously in the pyrroloquinoline
series,9a,b it was found that the yield of the ester was sub-
stantially lower ca. 62% versus >90%. This was due to
the formation of 30 (32%, Fig. 4) via a base-induced net
retro Michael reaction. It was found that the ratio of the de-
sired product and byproduct was dependent on the concen-
tration of the base (NaOAc). Decreasing the amount of the
NaOAc (0.8 equiv) led to the increased formation of 28 in
76%, however, further reduction in the amount of base
(0.6 equiv) employed led to a reduction in the yield of 28
(44%). Other bases were screened and it was determined
that Hunig’s base (diisopropylethylamine) provided satis-
factory results affording an excellent 86% yield of 28, and
a small quantity of 30 (12%). Preliminary scouting experi-
ments were performed in an attempt to remove both of the
Bn
Bn
N
N
Br
Br
a
c
2a
2
N
X
N
O
Bn
Bn
31: X = β-ΟH (98%)
32: X = α-ΟMe (98%)
cis-26
b
Bn
N
Bn
N
Br
Br
2a
+
2
N
Bn
N
Bn
34 (30%)
33
Bn
Bn
N
N
Br
BnHN
Br
MeO2C
N
Bn
N
Bn
+
N
Bn
O
35
36
30
Scheme 7. Reagents and conditions: (a) DIBAL-H, THF, ꢁ78 ꢀC; (b)
CHCl3, MeOH, reflux; (c) allyltrimethylsilane, TiCl4, CH2Cl2, ꢁ78 ꢀC.
Figure 4. Byproduct from the Pd-catalyzed carbonylation.

8760
Y. He et al. / Tetrahedron 62 (2006) 8755–8769
less hindered face, i.e., the opposite side to the cis-fused
pyrrolidine ring, leading to the formation of major diastereo-
isomer 34 in 30% yield (dr¼7:1 crude reaction mixture, in
the major isomer, relative stereochemistry was assigned
through an NOESYexperiment). The low yield of the desired
product was due to the formation of the b-elimination prod-
uct 35 (ca. 50%), which was relatively unstable and further
converted to the fully conjugated product 36. Other Lewis
acids were evaluated in this reaction, but with generally dis-
appointing results. For example Ti(OPr-i)4 was unreactive,
whereas MeAlCl2 gave the b-elimination product exclu-
sively, BF3$Et2O, on the other hand, led to complete decom-
position of the substrate. We attempted to elaborate 34 via
hydroboration and an oxidative work-up, a product was iso-
lated from this treatment that displayed spectroscopic prop-
erties consistent with the desired primary alcohol. However,
the efficiency was very loww30%, and the isolated material
was not very pure, therefore, we sought an alternative and
more efficient means to incorporate the C2-side chain.
prior to fragmentation.38 Indeed simply treating 32 with
TMSOTf led to the efficient formation of the quinolinium
ion (39, Scheme 9), a similar type of fragmentation has
been observed previously in related systems.8c,13a Signifi-
cant effort was expended in order to identify conditions
that permitted the introduction of the side chain via acetylide
chemistry using numerous modes of additions, a variety of
metal acetylides (Cu, Zn, Mg) and Lewis acids, all without
success. The use of 37 in the presence of AgBF4, as an alter-
native iminium ion precursor, was evaluated with various
metal acetylides, but met with no success.39
Bn
BnHN
N
Br
Br
TMSOTf
Cu
OMe
N
Bn
N
Bn
OTBS
OTBS
32
38 (70%)
TMSOTf
BnHN
Br
Although the desired allylation product was not obtained
from the majority of these reactions, the formation of
enamine 35 was consistent with the formation of the desired
reactive intermediate, iminium ion 33. Presumably allyl-
trimethylsilane is insufficiently nucleophilic to trap the
incipient iminium ion, which then results in alternative fates.
Bearing this in mind, we wished to establish an idea of the
general reactivity patterns of 33 and whether nucleophiles
could be identified that would react faster than competing
elimination, and so TMSCN was evaluated in this capacity.
We were delighted to find that when the a-methoxyaminol
32 was treated with 4 equiv of TMSCN at room temperature,
the desired cyano-substituted adduct 37 was obtained in an
excellent 95% yield within couple of hours (Scheme 8).
The reaction provided a single stereoisomer based on analy-
sis of the NMR spectrum of the crude reaction mixture. It
was found that reaction proceeds with essentially the same
facility with the aminol 31 under similar reaction conditions,
providing the same product in 90% (Scheme 8). In both
cases, the stereochemistry of the adduct appears to be exo
(based on an NOESY experiment), i.e., that required for an
approach to the natural product.36
+
N
Bn
39
Scheme 9.
Several options were open to us at this point, none of which
were particularly attractive until we became aware of Li’s
work, describing the in situ preparation of a copper acetylide
(terminal alkyne/CuBr) under aqueous conditions with soni-
cation in the absence of a Lewis acid (or other externally
added promoter).40 Presumably the heterogeneous condi-
tions keep the solution concentrations of all of the reagents
low thus minimizing side reactions, and the acid that is
produced on reaction of the acetylene with CuBr is sufficient
to ionize the a-methoxyamine 32. Gratifyingly, when Li’s
protocol was applied to 32 and the silyl-protected propargyl
alcohol derivative 40, the desired adduct 41 was obtained in
48% yield, along with 40% of the fragmentation product 38
(cf. Scheme 9), it was also found that the aminol 31 would
react analogously (Scheme 10).
Bn
Bn
Bn
Bn
N
N
N
N
Br
Br
a
Br
Br
TMSCN
CH2Cl2
N
Bn
N
Bn
X
N
CN
N
Bn
X
R = H (90%)
Bn
37
OTBS
R = Me (95%)
41 (48%)
31: X = β-ΟH
31: X = β-OH
32: X = α-ΟMe
32: X = α-OMe
OTBS
40
Scheme 8.
b
Encouraged by the fact that this silicon-based Lewis acid
successfully mediated the formation of the iminium ion,
which was then captured by CNꢁ, the use of TMSOTf in
combination with a three-carbon copper acetylide (prepared
from 40 and CuCl/Et3N) as nucleophile was investigated.37
As can be seen in Scheme 9, the addition took place
smoothly, but was complicated by a fragmentation of the
pyrrolidine ring to provide 38 in an unoptimized 70% yield
(Scheme 9). Apparently the combination of relatively low
electrophilicity of the iminium ion coupled with the aroma-
tization driving force (32/39, Scheme 9) thwarted addition
N BOC
CBZ
42
Bn
HN
Bn
N
Br
Br
N
Bn
N
Bn
N
N
43 (32%)
44 (~50%)
BOC
CBZ
BOC
CBZ
Scheme 10. Reagents and conditions: (a) CuBr, H2O, 40, ultrasound; (b)
CuBr, 42, H2O, ultrasound.

Y. He et al. / Tetrahedron 62 (2006) 8755–8769
8761
Encouraged by this result, it was decided to evaluate a pro-
pargyl amine derivative, thereby incorporating all of the
remaining carbon and the nitrogen atoms in one step. When
the doubly protected amine derivative 4241 was employed
under the Li’s conditions with 31, it was found that addition
took place, providing the required adduct 43 in 32% yield
along with the corresponding fragmentation product 44
(w50%). We were unable to isolate and fully characterize
the fragmentation product 44 as it co-eluted with unreacted
42 during column chromatography. Presumably, the two car-
bamate protecting groups attenuate the nucleophilicity of the
acetylide and thus the fragmentation pathway becomes more
dominant, thus lowering the yield of the desired adduct.
Rather than spending time trying to optimize this reaction,
however, it was decided to introduce the carboxymethyl
group in the aryl ring and then evaluate this as a substrate.
The rationale behind this approach rests on the electron
withdrawing effect of the methyl ester, which should
increase the electrophilicity of the iminium ion (in effect
a doubly vinylogous carbamate), and additionally it should
reduce the propensity of the system to fragment since it
would destabilize the developing positive charge at the
benzylic position. It was hoped that this modification would
lead to an increase in the proportion of the simple addition
product with respect to the fragmentation–addition product.
Incorporation of the methyl ester was readily achieved by
bromine/lithium exchange with 32, followed by quenching
of the organolithium with dimethyl carbonate, which gave
the desired product (32/45, Scheme 11). Gratifyingly,
when this material was treated with 42 under Li’s conditions,
the addition product 47 was obtained in 40%, along with the
fragmentation product in a comparable amount (w40%,
purification was again problematic due to co-elution of the
acetylene) estimated from the integration data obtained
from the 1H NMR spectrum of the crude product. Reductive
debenzylation, reduction of the alkyne, and acid hydrolysis
of the BOC group were achieved simultaneously by treat-
ment of 47 with Pd(OH)2 and H2 in the presence of HCl,
providing the tricyclic triamine 48 in 95% (ca. 90% purity)
as the hydrochloride salt, which we and others have con-
verted into martinellic acid and martinelline.10c,17a,b,42
In conclusion, an efficient approach for the synthesis and
elaboration of the pyrrolo[3,2-c]quinolone, the tricyclic
core of the Martinella alkaloids, have been developed via
a stereoselective intramolecular [3+2] azomethine ylide/
alkene cycloaddition approach. Conformational effects
play an important role in this and related intramolecular
cycloaddition processes investigated in this study. The
presence of an N-alkyl substituent is critical to the success
of this and related cycloaddition processes. In addition to
the desired pyrroloquinolones, various 1,2,3,4-tetrahydro-
quinolin-2-one and 1,2-dihydroquinolin-2-one derivatives
have also been synthesized via an interesting domino
Michael–Mannich reaction of N-alkylated substrates,
whereas the corresponding N–H substrates undergo only the
Michael portion of the sequence. An advanced precursor 47
for the total synthesis of the Martinella alkaloids was
obtained through an in situ acid mediated addition of a func-
tionalized copper acetylide to an iminium ion, though the
efficiency needs to be further improved. Global deprotection
with concomitant alkyne reduction provided the tricyclic
triamine 48 in good yield as the HCl salt.
2. Experimental
2.1. General
All chemicals and solvents were purchased from commercial
vendors and were used as received unless indicated other-
wise. All reactions involving air- or water-sensitive
compounds were conducted in oven-dried glassware under
an atmosphere of dry argon or nitrogen. A Pure-Solv 400 sol-
vent purification system from Innovative Technology Inc.
was also used to obtain anhydrous CH3CN, THF, CH2Cl2,
benzene, and toluene. NMR spectra were obtained on
a JEOL Eclipse+ 500 MHz; 1H NMR spectra were recorded
in deuteriochloroform (unless otherwise indicated) at a spec-
trometer frequency of 500.16 MHz, residual protiochloro-
form was used as internal reference; 13C NMR spectra
were obtained in deuteriochloroform (unless otherwise
indicated) at 125.79 MHz using 13CDCl3 (d¼77.0 ppm) as
internal reference. Infrared (IR) spectra were obtained on
a Bruker Vector 22 FT-IR spectrometer, using KBr pressed
pellets for solids or neat films on NaCl plate for liquids
and oils, and were reported in cmꢁ1. Electron impact mass
spectra (EIMS) were recorded in-house on a Bear Instru-
ments, Kodiak 1200 spectrometer (at 70 eV) and electro-
spray ionization mass spectra (ESIMS) and LC/MS were
recorded on an Agilent 1100 LC/MS system controlled by
Chemstation version 8.3. (the ESI condition is 4.5 kV spray
voltage with 10 mL minꢁ1 infusion) at HT Laboratories Inc.
High-resolution mass spectra (HRMS) were recorded using
electrospray ionization (ESI) time-of-flight reflectron experi-
ments performed on an Agilent ESI-TOF mass spectrometer
at the Center for Mass Spectrometry at the Scripps Research
Institute, La Jolla, California. Elemental analyses were per-
formed in-house on a Perkin–Elmer 2400 CHN Elemental
Analyzer or at Quantitative Technologies Inc. Melting points
were recorded on a Thomas Hoover Scientific capillary tube
Bn
Bn
N
N
Br
MeO2C
a
b
~90%
N
Bn
OMe
Bn
N
Bn
OMe
32
45
Bn
HN
N
N
MeO2C
MeO2C
c
N
Bn
Bn
N
N
CBZ
BOC
BOC
47 (40%)
CBZ
46 (~40%)
HN
.xHCl
NH2
MeO2C
d
1 and 2
N
H
48
Scheme 11. Reagents and conditions: (a) n-BuLi, THF, ꢁ78 ꢀC then
CO(OMe)2, ꢁ78/0 ꢀC; (b) CuBr, 42, H2O, ultrasound; (c) 20%
Pd(OH)2/C, MeOH, H2; (d) lit.7b,10c,17a

8762
Y. He et al. / Tetrahedron 62 (2006) 8755–8769
melting point apparatus and were uncorrected. Analytical
thin-layer chromatography (TLC) was performed on silica
gel 60 F254 aluminum backed precoated plates (layer thick-
ness¼200 mm). A Fisher Scientific sonicator (Model
FS20H, 3 qt., 120 V, 50/60 Hz, 1 A, 143 W, with heater)
was used in this work.
toluene (10 mL), then Et3N (0.13 mL, 0.95 mmol, 3 equiv)
was added. The resulting mixture was heated under reflux
for 2 h, at which time TLC analysis indicated the completion
of the reaction. The mixture was cooled to room tempera-
ture, diluted with EtOAc (10 mL), and washed with H2O
(2ꢂ15 mL) and brine (15 mL), dried (Na2SO4), and then
concentrated. The crude product was purified by chromato-
graphy (hexane/ethyl acetate, 2:1) to give the title compound
as a colorless solid (61 mg, 66%). Mp: 80–82 ꢀC. 1H NMR:
d¼7.35 (m, 1H), 7.12–7.26 (m, 6H), 7.03–7.06 (m, 2H), 4.02
(d, J¼13.1 Hz, 1H), 3.44 (s, 3H), 3.38 (d, J¼5.5 Hz, 1H),
3.14 (d, J¼13.1 Hz, 1H), 2.98 (m, 2H), 2.63 (m, 1H), 2.16
(m, 2H); 13C NMR: d¼171.7, 140.3, 139.5, 130.9, 129.2,
128.3, 128.1, 126.8, 122.8, 122.2, 114.8, 64.9, 57.4, 51.3,
43.6, 29.9, 26.2; IR: 3025, 2914, 2788, 1665, 1602; EIMS
(m/z): 292.4 (M+, 4), 291.1 (M+ꢁ1, 64), 200.0 (33), 185.0
(62), 158.9 (70). Anal. Calcd for C19H20N2O: C, 78.05; H,
6.89; N, 9.58. Found: C, 78.43; H, 7.12; N, 9.41.
2.1.1. N-(2-Hydroxymethylphenyl)-N-methylacrylamide
(12). Acryloyl chloride (0.33 mL, 4.04 mmol) was added
dropwise to a cooled suspension of the amino alcohol 11
(553 mg, 4.04 mmol) and sodium bicarbonate (400 mg,
4.76 mmol) in anhydrous CH2Cl2 (5 mL) and stirred for
1 h. The reaction mixture was then diluted with CH2Cl2
(5 mL) and washed with water (2ꢂ10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated. The crude oil
was re-dissolved in CH2Cl2 and hexane and concentrated
again. The process was repeated until a solid product was
obtained. Trituration of the solid with Et2O several times
provided pure 12 (686 mg, 89%) as a colorless solid. The
combined Et2O washings were concentrated and purification
of the resulting oil by chromatography (hexane/ethyl acetate,
4:1) gave additional N-acylated product (46 mg, 6%). Mp:
2.2.2. (3aS*,9bS*)-1-Benzyl-5-methyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinolin-4-one trans-(14a).
Eluted out right after the cis-adduct as brown oil (5 mg,
5%). 1H NMR: d¼7.49 (d, J¼7.3 Hz, 2H), 7.46 (d,
J¼7.3 Hz, 1H), 7.37 (dd, J¼7.8, 7.3 Hz, 2H), 7.28–7.32
(m, 2H), 7.11 (dd, J¼7.3, 7.3 Hz, 1H), 7.07 (d, J¼7.8 Hz,
2H), 4.48 (d, J¼14.2 Hz, 1H), 3.65 (d, J¼13.8 Hz, 1H),
3.49 (d, J¼14.2 Hz, 1H), 3.39 (s, 3H), 3.36 (ddd, J¼10.5,
8.3, 8.3 Hz, 1H), 2.76 (ddd, J¼14.0, 10.8, 8.3 Hz, 1H),
2.67 (ddd, J¼10.5, 10.1, 3.8 Hz, 1H), 2.01–2.12 (m, 2H);
13C NMR: d¼171.8, 140.6, 139.2, 131.3, 128.6, 128.4,
127.4, 127.2, 123.3, 122.3, 115.4, 64.4, 61.2, 55.2, 47.4,
29.8, 26.7; IR (neat, cmꢁ1): 3062, 3030, 2926, 1683, 1648,
1604; EIMS (m/z): 290.7 (M+ꢁ1, 74), 200.0 (76), 104.1
(30), 89.7 (100).
1
64–66 ꢀC. H NMR: d¼7.60 (d, J¼7.3 Hz, 1H), 7.41 (dd,
J¼7.6, 7.3 Hz, 1H), 7.36 (dd, J¼7.8, 7.6 Hz, 1H), 7.13 (d,
J¼7.8 Hz, 1H), 6.34 (dd, J¼16.8, 1.8 Hz, 1H), 5.90 (dd,
J¼16.8, 10.3 Hz, 1H), 5.48 (dd, J¼10.3, 1.8 Hz, 1H), 4.60
(m, 2H), 3.28 (s, 3H), 2.30 (br s, 1H); 13C NMR: d¼166.1,
140.8, 138.5, 129.1, 129.03, 128.97, 128.3, 128.2, 127.9,
60.8, 37.1; IR (KBr, cmꢁ1): 3401, 2873, 1650, 1613; EIMS
(m/z): 191.1 (M+, 18), 173.3 (19), 135.2 (40), 159.2 (100),
117.1 (84), 89.9 (34), 53.7 (32). Anal. Calcd for
C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.36;
H, 7.09; N, 7.32.
2.1.2. N-(2-Formylphenyl)-N-methylacrylamide (13). Al-
cohol 12 (150 mg, 0.78 mmol, 1 equiv) was dissolved in
DMSO (3 mL) and then IBX (330 mg, 1.18 mmol, 1.5 equiv)
was added and the reaction mixture was stirred at room tem-
perature for 1 h. The mixture was diluted with H2O. The
resulting precipitate was filtered and rinsed with H2O. The
aqueous layer was extracted with CH2Cl2 (3ꢂ). The com-
bined organic extracts were washed with brine (2ꢂ), dried
(Na2SO4), after concentration the crude product was passed
through a plug of SiO2 (CH2Cl2) and concentrated to afford
pure 13 as a thick oil (119 mg, 80%). 1H NMR: d¼10.07 (s,
1H), 7.99 (dd, J¼7.8, 1.4 Hz, 1H), 7.70 (ddd, J¼7.8, 7.3,
1.4 Hz, 1H), 7.54 (dd, J¼7.8, 7.3 Hz, 1H), 7.29 (d,
J¼7.8 Hz, 1H), 6.40 (dd, J¼16.7, 1.8 Hz, 1H), 5.87 (dd,
J¼16.7, 10.5 Hz, 1H), 5.54 (dd, J¼10.5, 1.8 Hz, 1H), 3.39
(s, 3H); 13C NMR: d¼189.2, 166.0, 145.4, 135.7, 132.9,
130.0, 129.4, 129.1, 129.0, 127.7, 38.4; IR (neat, cmꢁ1):
3055, 2918, 2850, 1695, 1656, 1596, 1265; EIMS (m/z):
189.3 (M+, 45), 159.2 (100), 133.0 (88), 105.0 (70), 75.9
(41), 53.7 (56). HRMS (m/z): calcd for MH+ C11H12NO2
190.0863, found 190.0868.
2.2.3. (3aR*,9bS*)-1,5-Dimethyl-2,3,3a,4,5,9b-hexa-
hydro-1H-pyrrolo[3,2-c]quinolin-4-one cis-(14b). Com-
pound 13 (210 mg, 1.11 mmol) and sarcosine (198 mg,
2.22 mmol, 2 equiv) were mixed in toluene (37 mL), then
Et3N (0.46 mL, 3.33 mmol, 3 equiv) was added. The mixture
was then heated under reflux for 5 h. After work-up (see syn-
thesis of 14a), chromatography (ethyl acetate/MeOH, 4:0.2)
gave the title compound as a colorless solid (140 mg, 58%).
Mp: 116–117 ꢀC. 1H NMR: d¼7.35 (ddd, J¼8.3, 7.3, 1.6 Hz,
1H), 7.17 (dd, J¼7.3, 1.6 Hz, 1H), 7.06 (ddd, J¼7.3, 7.3,
0.9 Hz, 1H), 7.02 (d, J¼8.3 Hz), 3.38 (s, 3H), 3.16 (m, 1H),
3.05 (d, J¼6.0 Hz, 1H), 2.98 (m, 1H), 2.66 (m, 1H), 1.98–
2.27 (m, 2H), 2.24 (s, 3H); 13C NMR: d¼171.6, 140.1,
130.6, 129.2, 122.2, 122.0, 114.8, 66.3, 54.5, 43.6, 40.0,
30.0, 26.5; IR (KBr, cmꢁ1): 2945, 2803, 1664, 1602; EIMS
(m/z): 216.3 (M+, 100), 199.2 (22), 186.1 (35), 173.0 (10).
Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95.
Found: C, 71.93; H, 7.50; N, 12.77.
2.3. Synthesis of 14c, 15c, and 16c
2.2. General procedure for azomethine ylide cycloaddi-
tion reactions
Compound 13 (60 mg, 0.32 mmol) and N-p-methoxybenzyl-
glycine hydrochloride (116 mg, 0.57 mmol, 1.8 equiv) were
mixed in anhydrous toluene (11 mL), then Et3N (0.13 mL,
0.95 mmol, 3 equiv) was added. The mixture was heated un-
der reflux for 10 h, at which time TLC analysis indicated the
completion of the reaction. The mixture was cooled to room
temperature, diluted with EtOAc (10 mL), and washed with
2.2.1. (3aR*,9bS*)-1-Benzyl-5-methyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinolin-4-one cis-(14a).
Compound 13 (60 mg, 0.32 mmol) and N-benzylglycine$HCl
(116 mg, 0.57 mmol, 1.8 equiv) were mixed in anhydrous

Y. He et al. / Tetrahedron 62 (2006) 8755–8769
8763
H2O (2ꢂ15 mL) and brine (15 mL), dried (Na2SO4), and
then concentrated. The crude oil was purified by chromato-
graphy (hexane/ethyl acetate, 2:1) to give cis-14c (16 mg,
16%), trans-14c (3 mg, 3%), byproduct 15c (12 mg, 11%),
and byproduct 16c (20 mg, 20%) in the order of elution
from the column. Following the above procedure, when an-
hydrous DMF (11 mL) was used instead of toluene and the
reaction was refluxed for 1 h instead of 10 h, after chromato-
graphy, cis-14c (45 mg, 44%), trans-14c (5 mg, 5%), and
byproduct 15c (11 mg, 10%) were obtained.
3.78 (s, 3H), 3.73 (s, 3H), 3.59 (s, 2H), 3.58 (s, 2H), 2.28
(s, 3H); 13C NMR: d¼162.3, 158.7, 139.1, 135.8, 131.3,
130.8, 130.1, 129.8, 128.6, 122.1, 120.8, 114.0, 113.7,
61.9, 55.8, 55.3, 42.7, 29.7; IR (neat, cmꢁ1): 3031, 2934,
2834, 1649, 1597; EIMS (m/z): 323.8 (M++1, 9), 201.4
(95), 174.7 (30), 149.7 (100), 130.1 (20), 79.8 (12). HRMS
(m/z): calcd for MH+ C20H23N2O2 323.1754, found
323.1756.
2.4. Control experiments
2.3.1. (3aR*,9bS*)-1-(4-Methoxybenzyl)-5-methyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-4-
Compound 13 (150 mg, 0.79 mmol) and HNMeBn
(0.20 mL, 1.55 mmol, 2 equiv) were mixed in anhydrous
DMF (27 mL), then Et3N (0.33 mL, 2.37 mmol, 3 equiv)
was added followed by addition of H2O (71 mg,
3.95 mmol). The mixture was heated at 150 ꢀC for 1.5 h.
The solvent was completely removed by vacuum distillation
and the residue was dissolved in EtOAc (30 mL) and washed
with H2O (2ꢂ15 mL) and brine (15 mL), dried (Na2SO4),
and then concentrated. The crude product was purified by
chromatography (hexane/ethyl acetate, 1:1) to give 15a
(220 mg, 90%). When the same reaction was conducted in
the absence of water and heated at 150 ꢀC for 8 h, 16a
(206 mg, 90%) was obtained after chromatography (hex-
ane/ethyl acetate, 1:1).
1
one cis-(14c). A colorless solid. Mp: 94–95 ꢀC. H NMR:
d¼7.35 (ddd, J¼7.8, 7.8, 1.4 Hz, 1H), 7.23 (dd, J¼7.3,
1.4 Hz, 1H), 7.03–7.06 (m, 4H), 6.74 (d, J¼8.7 Hz, 2H),
3.95 (d, J¼12.8 Hz, 1H), 3.75 (s, 3H), 3.43 (s, 3H), 3.36 (d,
J¼5.5 Hz, 1H), 3.07 (d, J¼12.8 Hz, 1H), 2.92–2.99 (m,
2H), 2.59–2.62 (m, 1H), 2.11–2.19 (m, 2H); 13C NMR:
d¼171.7, 158.5, 140.3, 131.5, 130.9, 129.4, 129.1, 122.8,
122.2, 114.8, 113.5, 64.8, 56.8, 55.3, 51.2, 43.6, 29.9, 26.2;
IR (KBr, cmꢁ1): 3039, 3006, 2924, 1662, 1604; EIMS
(m/z): 322.1 (M+, 35), 279.1 (28), 201.2 (21), 167.1 (30),
149.1 (98), 136.3 (40), 121.2 (100). Anal. Calcd for
C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.45;
H, 6.84; N, 8.96.
2.4.1. (3R*,4R*)-4-(Benzylmethylamino)-3-hydroxy-
methyl-1-methyl-3,4-dihydro-1H-quinolin-2-one (15a).
A colorless solid. Mp: 94–95.5 ꢀC. 1H NMR: d¼7.86 (br s,
1H), 7.62 (d, J¼7.3 Hz, 1H), 7.26–7.36 (m, 5H), 7.16 (dd,
J¼7.8, 7.3 Hz, 1H), 6.96 (d, J¼7.8 Hz, 1H), 4.84 (d, J¼
12.1 Hz, 1H), 3.76 (d, J¼12.8 Hz, 1H), 3.48 (d, J¼12.8 Hz,
1H), 3.32 (s, 3H), 3.27 (dd, J¼13.1, 3.4 Hz, 1H), 3.04 (d,
J¼13.1, 11.9 Hz, 1H), 2.81 (ddd, J¼12.1, 11.9, 3.4 Hz,
1H), 2.29 (s, 3H); 13C NMR: d¼169.1, 137.7, 137.3, 129.9,
129.3, 128.7, 128.1, 127.7, 124.3, 123.7, 114.3, 70.9, 63.1,
58.5, 42.5, 29.9; IR (neat, cmꢁ1): 3062, 3029, 2951, 2854,
2801, 1669, 1605; EIMS (m/z): 310.9 (M+, 22), 220.0 (95),
201.5 (13), 176.8 (100), 159.6 (15), 134.4 (28), 120.3 (9),
91.9 (12). Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14;
N, 9.03. Found: C, 73.51; H, 6.96, N, 9.36.
2.3.2. (3aS*,9bS*)-1-(4-Methoxybenzyl)-5-methyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-
4-one trans-(14c). Colorless oil. 1H NMR: d¼7.46 (d,
J¼7.3 Hz, 1H), 7.39 (d, J¼8.7 Hz, 2H), 7.30 (dd, J¼7.3,
7.3 Hz, 1H), 7.11 (dd, J¼7.8, 7.3 Hz, 1H), 7.06 (d, J¼
7.8 Hz, 1H), 6.90 (d, J¼8.7 Hz, 2H), 4.40 (d, J¼14.2 Hz,
1H), 3.82 (s, 3H), 3.62 (d, J¼13.8 Hz, 1H), 3.42 (d,
J¼14.2 Hz, 1H), 3.39 (s, 3H), 3.31 (ddd, J¼10.5, 8.3,
8.3 Hz, 1H), 2.74 (ddd, J¼13.8, 10.5, 8.3 Hz, 1H), 2.67
(ddd, J¼10.5, 10.1, 4.1 Hz, 1H), 2.00–2.12 (m, 2H); 13C
NMR: d¼171.8, 158.9, 140.6, 131.3, 131.1, 129.6, 127.4,
123.3, 122.4, 115.4, 113.9, 64.3, 60.5, 55.4, 55.0, 47.4,
29.9, 22.6; IR (neat, cmꢁ1): 3032, 2962, 2923, 2853, 2839,
1683, 1605. EIMS (m/z): 322.0 (M+, 31), 201.1 (42), 179.1
(59), 121.1 (100).
2.4.2. 3-[(Benzylmethylamino)methyl]-1-methyl-1H-qui-
1
2.3.3. (3R*,4R*)-3-Hydroxymethyl-4-[(4-methoxybenz-
yl)methylamino]-1-methyl-3,4-dihydro-1H-quinolin-2-
one (15c). Brown oil. 1H NMR: d¼7.61 (d, J¼7.8 Hz, 1H),
7.29 (dd, J¼7.8, 7.3 Hz, 1H), 7.24 (d, J¼8.7 Hz, 2H), 7.16
(dd, J¼7.3, 7.3 Hz, 1H), 6.96 (d, J¼7.3 Hz, 1H), 6.87 (d,
J¼8.7 Hz, 2H), 4.82 (d, J¼12.4 Hz, 1H), 3.79 (s, 3H),
3.70 (d, J¼12.8 Hz, 1H), 3.41 (d, J¼12.8 Hz, 1H), 3.31 (s,
3H), 3.23 (dd, J¼12.8, 3.7 Hz, 1H), 3.03 (dd, J¼12.8,
11.9 Hz, 1H), 2.80 (ddd, J¼12.4, 11.9, 3.7 Hz, 1H), 2.28
(s, 3H); 13C NMR: d¼169.1, 159.1, 137.7, 130.6, 129.9,
129.3, 128.0, 124.2, 123.7, 114.3, 114.0, 70.9, 62.4, 58.2,
55.3, 42.5, 42.0, 29.8; IR (neat, cmꢁ1): 2965, 2923, 2856,
1669, 1604; EIMS (m/z): 340.2 (M+, 8), 219.2 (19), 201.2
(59), 172.2 (21), 150.2 (100), 121.1 (68), 84.0 (16).
nolin-2-one (16a). Brown oil. H NMR: d¼7.93 (s, 1H),
7.60 (d, J¼7.8 Hz, 1H), 7.55 (dd, J¼8.3, 7.3 Hz, 1H),
7.39–7.43 (m, 2H), 7.30–7.38 (m, 3H), 7.23–7.26 (m, 2H),
3.74 (s, 3H), 3.68 (s, 2H), 3.63 (s, 2H), 2.31 (s, 3H); 13C
NMR: d¼162.3, 139.1, 135.9, 130.5, 129.9, 129.0, 128.6,
128.4, 127.1, 122.1, 120.8, 113.9, 62.5, 56.0, 42.7, 29.7;
IR (neat, cmꢁ1): 3062, 3028, 2938, 2841, 2783, 1649,
1597; EIMS (m/z): 293.8 (M++1, 21), 202.0 (100), 187.9
(10), 173.1 (50), 120.7 (50). HRMS (m/z): calcd for MH+
C19H21N2O 293.1648, found 293.1647.
2.4.3. (2-Benzylamino-5-bromophenyl)methanol (23).
Benzoyl chloride (0.28 mL, 2.39 mmol, 1.1 equiv) was
added dropwise to a cooled suspension of the methyl 5-ami-
no-2-bromobenzoate (6) (500 mg, 2.17 mmol, 1 equiv) and
sodium bicarbonate (365 mg, 4.35 mmol, 2 equiv) in
CH2Cl2 (4 mL) at 0 ꢀC. The reaction mixture was allowed
to warm up to room temperature and stirred for 5 h then
diluted with CH2Cl2 (10 mL) and washed with water
(2ꢂ15 mL) and brine (15 mL), dried (Na2SO4), and
2.3.4. 3-{[(4-Methoxybenzyl)methylamino]methyl}-
1-methyl-1H-quinolin-2-one (16c). Pale yellow oil. 1H
NMR: d¼7.88 (s, 1H), 7.60 (d, J¼7.8 Hz, 1H), 7.58 (dd, J¼
8.3, 7.3 Hz, 1H), 7.33 (d, J¼8.3 Hz, 1H), 7.31 (d, J¼8.7 Hz,
2H), 7.23 (dd, J¼7.8, 7.3 Hz, 1H), 6.86 (d, J¼8.7 Hz, 2H),

8764
Y. He et al. / Tetrahedron 62 (2006) 8755–8769
evaporated to dryness. Purification of the crude product by
trituration with Et2O gave benzamide32 (706 mg, 97%) as
1582; EIMS (m/z): 345.1 (M++2, 11), 343.0 (M+, 11),
290.1 (100), 288.1 (92), 209.2 (27), 179.9 (28). Anal. Calcd
for C17H14BrNO2: C, 59.32; H, 4.10; N, 4.07. Found: C,
59.60; H, 4.21; N, 3.95.
1
a colorless solid. Mp: 130–132 ꢀC. H NMR: d¼11.97 (br
s, 1H), 8.87 (d, J¼9.2 Hz, 1H), 8.02 (d, J¼2.8 Hz, 2H),
7.69 (dd, J¼9.2, 2.8 Hz, 1H), 7.50–7.56 (m, 3H), 3.98 (s,
3H); 13C NMR: d¼168.0, 165.8, 141.0, 137.6, 134.6,
133.6, 132.3, 129.0, 127.5, 122.2, 116.8, 115.1, 52.9.
2.4.6. (3aR*,9bS*)-8-Bromo-1,5-dibenzyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinolin-4-one cis-(26).
Benzaldehyde 25 (800 mg, 2.32 mmol) and N-benzyl-
glycine$HCl (844 mg, 4.18 mmol) were dissolved in anhy-
drous toluene (80 mL), then Et3N (0.97 mL, 6.97 mmol)
was added to the mixture. The resulting mixture was stirred
under reflux for 2 h. After this period the mixture was cooled
to room temperature, then diluted with EtOAc (10 mL). The
organic phase was washed with H2O (2ꢂ10 mL) and brine
(10 mL), dried (Na2SO4), and then concentrated by rotary
evaporation. The crude oil, which solidified after coevapora-
tion with CH2Cl2/hexane, was triturated with Et2O several
times to provide pure solid product cis-26 (363 mg, 35%).
The Et2O washings were concentrated and purified by chro-
matography (hexane/ethyl acetate, 5:1) to give an additional
batch of cis-26 as a white solid (166 mg, 16%) Total yield:
A solution of the benzamide (650 mg, 1.95 mmol) in THF
(5 mL) was added dropwise at ꢁ9 ꢀC (ice/methanol) to a
suspension of LiAlH4 (406 mg, 10.7 mmol) in THF (12 mL).
The reaction mixture was then allowed to warm up to room
temperature and continued stirring overnight. Reaction was
then quenched by H2O (1 mL), NaOH (15%, 1 mL), and
Rochelle’s salt (20%, 5 mL). The resulting white slurry
was filtered and then the filtrate was concentrated under
vacuum. The filter cake was washed thoroughly by EtOAc
(4ꢂ5 mL). The extract was combined with concentrated fil-
trate and washed with brine. After drying (Na2SO4), concen-
trating under vacuum, the residue was purified by flash
chromatography (hexane/ethyl acetate, 4:1) to provide the
title compound 23 (530 mg, 93%) as colorless oil. 1H NMR:
d¼7.32–7.36 (m, 4H), 7.25–7.29 (m, 1H), 7.23 (dd, J¼8.7,
2.3 Hz, 1H), 7.19 (d, J¼2.3 Hz, 1H), 6.50 (d, J¼8.7 Hz,
1H), 5.20 (br s, 1H), 4.64 (s, 2H), 4.36 (s, 2H), 1.56 (br s,
1H); 13C NMR: d¼146.4, 139.0, 132.1, 131.6, 128.8, 127.4,
127.3, 126.2, 112.7, 108.3, 64.3, 47.8; IR (neat, cmꢁ1):
3555, 3407, 3062, 3029, 2870, 1598; EIMS (m/z): 293.0
(M++1, 49), 291.1 (M+ꢁ1, 44), 213.2 (100), 194.2 (78).
1
51%. Mp: 139–140 ꢀC. H NMR: d¼7.32 (d, J¼2.3 Hz,
1H), 7.16–7.30 (m, 11H), 6.80 (d, J¼8.7 Hz, 1H), 5.59 (d,
J¼16.5 Hz, 1H), 4.98 (d, J¼16.5 Hz, 1H), 4.01 (d, J¼
12.8 Hz, 1H), 3.40 (d, J¼5.0 Hz, 1H), 3.19 (d, J¼12.8 Hz,
1H), 3.04–3.12 (m, 2H), 2.72–2.78 (m, 1H), 2.16–2.28 (m,
2H); 13C NMR: d¼171.4, 139.1, 138.2, 136.5, 133.5,
131.9, 128.8, 128.3, 128.2, 127.2, 127.0, 126.6, 125.2,
117.5, 114.9, 64.8, 57.6, 51.2, 45.4, 43.7, 26.0; IR (KBr,
cmꢁ1): 2802, 1669; EIMS (m/z): 448.2 (M++2, 24), 446.1
(M+, 28), 356.9 (14), 354.9 (13), 314.0 (16), 201.2 (12),
150.2 (14), 133.2 (28), 91.1 (100), 65.0 (15), 35.9 (17).
Anal. Calcd for C25H23BrN2O: C, 67.12; H, 5.18; N, 6.26.
Found: C, 67.44; H, 5.23; N, 6.10.
2.4.4. N-Benzyl-N-(4-bromo-2-hydroxymethylphenyl)-
acrylamide (24). Following the general procedure for
N-acrylation described for compound 12, amino alcohol 23
(1.03 g, 3.53 mmol) was used, and then purification of the
crude oil by chromatography (hexane/ethyl acetate, 3:2)
gave the N-acylated product 24 (1.09 g, 89%). Mp: 76–
77 ꢀC. 1H NMR: d¼7.71 (d, J¼2.3 Hz, 1H), 7.40 (dd,
J¼8.3, 2.3 Hz, 1H), 7.26–7.28 (m, 3H), 7.21–7.18 (m, 2H),
6.78 (d, J¼8.3 Hz, 1H), 6.44 (dd, J¼17.0, 1.8 Hz, 1H),
5.84 (dd, J¼17.0, 10.1 Hz, 1H), 5.56 (dd, J¼10.1, 1.8 Hz,
1H), 4.92 (d, J¼14.2 Hz, 1H), 4.85 (d, J¼14.2 Hz, 1H),
4.28 (dd, J¼13.8, 6.4 Hz, 1H), 4.14 (dd, J¼13.8, 5.5 Hz,
1H), 1.30 (dd, J¼6.4, 5.5 Hz, 1H); 13C NMR: d¼165.5,
141.4, 137.6, 136.6, 132.2, 131.9, 130.8, 129.6, 129.4,
128.7, 128.0, 127.7, 123.0, 60.2, 52.8; IR (KBr, cmꢁ1):
3321, 3094, 3055, 3023, 1642, 1608; EIMS (m/z): 347.0
(M++2, 40), 345.8 (M+, 28), 329.2 (100), 273.1 (34), 193.1
(21), 117.1 (11), 91.0 (92), 55.0 (37). Anal. Calcd for
C17H16BrNO2: C, 58.97; H, 4.66; N, 4.05. Found: C, 59.15;
H, 4.90; N, 3.96.
2.4.7. (3aS*,9bS*)-8-Bromo-1,5-dibenzyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinolin-4-one trans-(26).
The trans-diastereoisomer eluted out immediately after the
cis-cycloadduct as a colorless solid (73 mg, 7%). Mp: 185–
1
186 ꢀC. H NMR: d¼7.52 (d, J¼2.3 Hz, 1H), 7.48–7.50
(m, 2H), 7.1–7.38 (m, 9H), 7.30–7.33 (m, 3H), 7.23–7.26
(m, 2H), 7.19–7.20 (m, 2H), 6.83 (d, J¼8.7 Hz, 1H), 5.24
(d, J¼16.3 Hz, 1H), 5.11 (d, J¼16.3 Hz, 1H), 4.41 (d,
J¼14.0 Hz, 1H), 3.70 (d, J¼13.8 Hz, 1H), 3.53 (d, J¼
14.0 Hz, 1H), 3.37 (ddd, J¼10.5, 8.3, 8.3 Hz, 1H), 2.90
(ddd, J¼14.0, 10.8, 8.0 Hz, 1H), 2.72 (ddd, J¼10.5, 10.5,
3.4 Hz, 1H), 2.05–2.20 (m, 2H); 13C NMR: d¼171.5,
138.8, 138.7, 136.7, 133.7, 130.2, 128.9, 128.7, 128.4,
127.4, 126.6, 125.7, 117.9, 116.5, 64.4, 61.2, 55.2, 47.4,
46.1, 22.7; IR (KBr, cmꢁ1): 3029, 2880, 1689; EIMS (m/z):
448.2 (M++3, 25), 447.2 (M++2, 27), 446.1 (M++1, 26),
445.0 (M+, 28), 357.1 (87), 354.9 (100), 329.0 (12), 326.9
(15), 277.1 (17), 91.1 (73), 65.0 (12). Anal. Calcd for
C25H23BrN2O: C, 67.12; H, 5.18; N, 6.26. Found: C, 67.34;
H, 5.22; N, 6.19.
2.4.5. N-Benzyl-N-(4-bromo-2-formylphenyl)acrylamide
(25). Following the general procedure for the IBX-oxidation
described for compound 13, alcohol 24 (4.00 g, 11.5 mmol)
1
provided aldehyde 25 (3.57 g, 90%). Mp: 112–113 ꢀC. H
NMR: d¼9.45 (s, 1H), 8.00 (d, J¼2.3 Hz, 1H), 7.73 (dd,
J¼8.4, 2.3 Hz, 1H), 7.26–7.28 (m, 3H), 7.14–7.16 (m, 2H),
7.00 (d, J¼8.4 Hz, 1H), 6.45 (dd, J¼16.5, 1.8 Hz, 1H),
5.80 (dd, J¼16.5, 10.1 Hz, 1H), 5.60 (dd, J¼10.1, 1.8 Hz,
1H), 5.10 (d, J¼13.8 Hz, 1H), 4.87 (d, J¼13.8 Hz, 1H);
13C NMR: d¼187.4, 165.3, 141.3, 138.2, 135.4, 134.5,
132.2, 131.7, 130.4, 129.6, 128.9, 128.4, 127.6, 123.3,
54.0; IR (KBr, cmꢁ1): 3083, 2871, 1938, 1690, 1653, 1616,
2.4.8. 1-Benzyl-3-[(benzylmethylamino)methyl]-6-
bromo-1H-quinolin-2-one (27). Compound 27 eluted out
immediately after trans-26 as brown oil (166 mg, 16%).
1H NMR: d¼7.91 (s, 1H), 7.74 (d, J¼2.3 Hz, 1H), 7.44
(dd, J¼9.2, 2.3 Hz, 1H), 7.42 (d, J¼7.3 Hz, 2H), 7.33–
7.36 (m, 3H), 7.23–7.31 (m, 4H), 7.17 (d, J¼7.3 Hz, 2H),
7.11 (d, J¼9.2 Hz, 1H), 5.53 (br s, 2H), 3.70 (s, 2H), 3.67

Y. He et al. / Tetrahedron 62 (2006) 8755–8769
8765
(s, 2H), 2.34 (s, 3H); 13C NMR: d¼162.1, 139.3, 137.4,
136.2, 134.9, 132.5, 132.3, 130.8, 129.0, 128.9, 128.4,
127.5, 127.2, 126.7, 122.6, 116.6, 115.0, 62.6, 55.9, 46.3,
42.9; IR (neat, cmꢁ1): 3062, 3029, 2943, 2840, 2787,
1650, 1620, 1590; EIMS (m/z): 446.3 (M+, 7), 357.1 (100),
355.0 (86), 238.0 (8), 235.9 (12), 235.9 (11), 120.1 (60),
91.0 (98). Anal. Calcd for C25H23BrN2O: C, 67.12; H,
5.18; N, 6.26. Found: C, 67.20; H, 4.92; N, 6.10.
MeOH and filtered through Celite and the Celite pad was
washed several times with MeOH. The combined filtrates
were concentrated and the residue was dissolved in saturated
NaHCO3 solution (8 mL), extracted with CH2Cl2 three
times. The organic extract was dried and evaporated. The
residue was purified through a short silica gel plug (ethyl
acetate/MeOH, 4:0.2) to give 29 as a colorless solid
(37 mg, 95%). Mp: 127–129 ꢀC. 1H NMR: d¼8.05 (d,
J¼2.3 Hz, 1H), 7.82 (dd, J¼8.7, 2.3 Hz, 1H), 7.17–7.31
(m, 5H), 6.90 (d, J¼8.7 Hz, 1H), 5.33 (d, J¼16.5 Hz, 1H),
5.15 (d, J¼16.5 Hz, 1H), 4.27 (d, J¼6.0 Hz, 1H), 3.86 (s,
3H), 3.14 (ddd, J¼8.7, 6.4, 4.1 Hz, 1H), 3.05 (m, 2H),
2.56 (m, 1H), 2.35 (m, 1H), 1.90 (br s, 1H); 13C NMR:
d¼171.4, 166.5, 142.4, 136.4, 130.9, 130.6, 128.9, 127.3,
126.3, 124.6, 124.4, 115.5, 58.4, 52.1, 46.4, 44.3, 44.2,
29.7; IR (KBr, cmꢁ1): 2950, 1715, 1675, 1610; EIMS
(m/z): 336.0, 294.2 (100) (M+, 85), 216.2 (39), 128.2 (24),
91.1 (86). Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99;
N, 8.33. Found: C, 71.28; H, 6.02; N, 8.26.
2.4.9. (3aR*,9bS*)-1,5-Dibenzyl-2,3,3a,4,5,9b-hexahy-
dro-1H-pyrrolo[3,2-c]quinolin-4-one-8-carboxylic acid
methyl ester (28). cis-26 (100 mg, 0.22 mmol), Pd(OAc)2
(16 mg, 0.07 mmol, 0.3 equiv), PPh3 (19 mg, 0.07 mmol,
0.33 equiv), N,N-diisopropylethylamine (23 mg, 0.18 mmol,
0.8 equiv), anhydrous MeOH (1.5 mL), and anhydrous
DMF (1.5 mL) were added to a high pressure reaction
tube, which was connected to a Teflon screw cap fitted
with a pressure gauge. The reaction mixture was pressurized
with CO, purged 4–6 times with CO, and then heated to
100 ꢀC with stirring for 24 h at 75 psi of CO. After cooling
down to the room temperature, the mixture was diluted
with CH2Cl2 and filtered through Celite and the Celite pad
was washed several times with CH2Cl2. The combined fil-
trates were washed 3–4 times with water. The organic phase
was dried and evaporated to dryness. The residue was puri-
fied by chromatography (hexane/ethyl acetate, 4:1) to give
the ester 28 (81 mg, 86%) and the byproduct 30 (12 mg,
2.4.12. (3aR*,4R*,9bS*)-8-Bromo-1,5-dibenzyl-
2,3,3a,4,5,9b-hexahydro-4-hydroxy-1H-pyrrolo[3,2-
c]quinoline (31). DIBAL-H (1 M in hexanes, 2.68 mL,
2.68 mmol) was added dropwise to a solution of lactam
cis-26 (600 mg, 1.34 mmol) in anhydrous THF (6.2 mL) at
ꢁ78 ꢀC and stirred for 4 h at ꢁ78 ꢀC. The reaction was
then quenched by dropwise addition of MeOH (2.4 mL) at
the same temperature. Rochelle’s salt (20%, 6 mL) and water
(6 mL) were added and mixture was warmed up to room tem-
perature. The aqueous solution was extracted with CH2Cl2
(3ꢂ15 mL). The organic layers were dried and evaporated
to provide the pure product 26 (592 mg, 98%, a 87:13 mix-
ture of two diastereomers) as a colorless solid after drying
under vacuum overnight, which was stored at ꢁ20 ꢀC. Data
for the major endo isomer: mp: 133–135 ꢀC. 1H NMR:
d¼7.19–7.34 (m, 12H), 6.91 (d, J¼9.9 Hz, 1H), 6.49 (d,
J¼8.9 Hz, 1H), 4.72 (dd, J¼9.9, 3.2 Hz, 1H), 4.71 (d, J¼
17.4 Hz, 1H), 4.66 (d, J¼17.4 Hz, 1H), 4.43 (d, J¼12.1 Hz,
1H), 3.39 (d, J¼4.4 Hz, 1H), 3.07 (d, J¼12.1 Hz, 1H), 2.90
(m, 1H), 2.69 (m, 1H), 2.18 (m, 1H), 2.02–2.09 (m, 2H);
13C NMR: d¼142.3, 138.6, 138.3, 134.6, 132.4, 128.8,
128.60, 128.57, 127.3, 127.1, 126.5, 120.1, 114.9, 108.5,
84.3, 64.4, 57.8, 54.3, 51.2, 38.9, 24.2; IR (neat, cmꢁ1):
3028, 2949, 2806, 1594; EIMS (m/z): 450.0 (M++2, 7),
448.1 (M+, 9), 432.0 (11), 430.0 (11), 358.8 (79), 356.9
(71), 312.9 (100), 310.9 (94).
1
13%). Data for 28: a colorless solid. Mp: 157–158 ꢀC. H
NMR: d¼7.90 (d, J¼2.0 Hz, 1H), 7.86 (dd, J¼8.3, 2.0 Hz,
1H), 7.26–7.30 (m, 4H), 7.20–7.24 (m, 3H), 7.14–7.18 (m,
3H), 6.98 (d, J¼8.3 Hz, 1H), 5.66 (d, J¼16.6 Hz, 1H),
5.02 (d, J¼16.6 Hz, 1H), 3.99 (d, J¼12.7 Hz, 1H), 3.87 (s,
3H), 3.50 (d, J¼4.9 Hz, 1H), 3.20 (d, J¼12.7 Hz, 1H),
3.14 (m, 1H), 3.07 (m, 1H), 2.78 (m, 1H), 2.22 (m, 2H);
13C NMR: d¼171.8, 166.5, 143.0, 139.1, 136.4, 132.3,
130.9, 128.8, 128.3, 128.2, 127.2, 126.9, 126.6, 123.9,
122.9, 115.5, 64.9, 57.5, 52.1, 51.2, 45.5, 43.8, 26.0; IR
(KBr, cmꢁ1): 3029, 2951, 2804, 1717, 1678, 1612; EIMS
(m/z): 426.1 (M+, 100), 335.2 (25), 320.2 (25), 294.2 (20),
133.2 (58), 91.1 (49). Anal. Calcd for C27H26N2O3: C,
76.03; H, 6.14; N, 6.57. Found: C, 75.94; H, 6.30; N, 6.45.
2.4.10. 1-Benzyl-3-(2-benzylaminoethyl)-1H-quinolin-
2-one-6-carboxylic acid methyl ester (30). Brown oil. H
1
NMR: d¼8.21 (d, J¼1.8 Hz, 1H), 8.00 (dd, J¼8.8, 1.8 Hz,
1H), 7.64–7.67 (m, 2H), 7.46 (m, 1H), 7.21–7.34 (m, 7H),
7.18 (d, J¼7.3 Hz, 2H), 5.57 (br s, 2H), 3.91 (s, 3H), 3.85
(s, 2H), 3.01 (t, J¼6.9 Hz, 2H), 2.92 (t, J¼6.9 Hz, 2H);
13C NMR: d¼166.4, 162.8, 141.7, 140.5, 136.6, 136.1,
132.8, 130.4, 130.3, 130.0, 128.5, 128.3, 127.5, 127.0,
126.7, 124.0, 120.4, 114.8, 53.9, 52.3, 47.9, 46.6, 31.8; IR
(neat, cmꢁ1): 1718, 1650, 1601; EIMS (m/z): 426.1 (M+,
6), 424.1 (8), 335.5 (22), 319.0 (13), 277.9 (100), 229.5
(14), 217.1 (34), 183.4 (24), 119.8 (53), 90.1 (50).
2.4.13. (3aR*,4S*,9bS*)-8-Bromo-1,5-dibenzyl-
2,3,3a,4,5,9b-hexahydro-4-methoxy-1H-pyrrolo[3,2-
c]quinoline (32). The diastereomeric mixture of aminals 31
(459 mg, 1.02 mmol) directly from last step was dissolved in
CHCl3 (4.5 mL) and MeOH (18 mL) and then heated to
reflux under N2 for 4 h. The solvents were completely re-
moved and the crude product was further dried under high
vacuum to provide the pure methoxyaminal 32 (463 mg,
98%) as a light brown semi-solid, which was stored at
ꢁ20 ꢀC and used without any further purification. 1H
NMR: d¼7.40–7.39 (m, 2H), 7.28–7.34 (m, 2H), 7.22–7.26
(m, 2H), 7.11 (dd, J¼8.7, 2.3 Hz, 1H), 6.48 (d, J¼8.7 Hz,
1H), 4.82 (d, J¼16.3 Hz, 1H), 4.51 (d, J¼16.3 Hz, 1H),
4.36 (d, J¼16.3 Hz, 1H), 4.36 (d, J¼2.1 Hz, 1H), 4.04 (d, J¼
12.8 Hz, 1H), 3.62 (d, J¼8.5 Hz, 1H), 3.38 (d, J¼12.8 Hz,
1H), 3.26 (s, 3H), 2.87–2.96 (m, 2H), 2.31 (ddd, J¼9.4,
2.4.11. (3aR*,9bS*)-5-Benzyl-2,3,3a,4,5,9b-hexahydro-
1H-pyrrolo[3,2-c]quinolin-4-one-8-carboxylic acid
methyl ester (29). Compound 28 (50 mg, 0.12 mmol) was
dissolved in methanol (4 mL) under nitrogen. Pd(OH)2/C
(20%) (8 mg, 0.01 mmol, 10 mol %.) and four drops of
concd HCl (ca. 0.04 mL, 0.44 mmol) were added to it. The
reaction flask was purged with H2 and then stirred under a
hydrogen balloon for 24 h. The mixture was diluted with

8766
Y. He et al. / Tetrahedron 62 (2006) 8755–8769
9.4, 6.9 Hz, 1H), 2.06 (m, 1H), 1.83 (m, 1H); 13C NMR:
d¼142.4, 140.0, 138.4, 132.52, 132.46, 130.8, 129.0,
128.8, 128.7, 128.3, 127.2, 127.0, 115.5, 110.9, 95.1, 61.7,
58.9, 55.3, 55.0, 52.0, 43.1, 28.4; IR (neat, cmꢁ1): 3027,
2928, 2806, 1592; EIMS (m/z): 464.2 (M++2, 3), 462.2
(M+, 24), 373.0 (100), 371.0 (99), 312.9 (78), 310.9 (59),
106.2 (45), 105.2 (33), 86.0 (32), 84.0 (50).
1H), 7.68 (d, J¼9.3 Hz, 1H), 7.21–7.46 (m, 11H), 5.94 (s,
2H), 5.14 (s, 2H), 4.30 (t, J¼8.8 Hz, 2H), 3.59 (t, J¼
8.8 Hz, 2H), 1.85 (br s, 1H); 13C NMR: d¼158.4, 141.5,
139.0, 137.3, 134.2, 133.6, 129.9, 129.4, 128.9, 128.7,
127.9, 126.2, 122.1, 120.5, 119.5, 115.7, 58.7, 58.1, 54.1,
24.5; IR (neat, cmꢁ1) 3400, 3031, 2943, 1637, 1609.
HRMS (m/z): calcd for M+ C25H2279BrN2+ 429.0961, found
429.0959; calcd for M+ C25H2281BrN2+ 431.0941, found
431.0944.
2.4.14. (3aR*,4S*,9bS*)-4-Allyl-8-bromo-1,5-dibenzyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline
(34). A solution of TiCl4 (0.38 mL, 3.43 mmol) in anhydrous
CH2Cl2 (3.4 mL) was added dropwise to a stirred solution of
methoxyaminal 32 (265 mg, 0.57 mmol) and allyltrimethyl-
silane (1.09 mL, 6.86 mmol) in anhydrous CH2Cl2 (12 mL)
at ꢁ78 ꢀC. The reaction mixture was allowed to warm up to
room temperature slowly and stirred overnight. An NaOH
solution (1 N, 20 mL) was added carefully to the reaction
mixture and the organic phase was separated. The aqueous
layer was further extracted with CH2Cl2 (2ꢂ). The com-
bined organic layers were dried (Na2SO4) and concentrated.
An 1H NMR spectrum of the crude reaction mixture showed
the formation of 34 and 35 in a ratio of ca. 0.6:1. The residue
was purified by chromatography (hexane/ethyl acetate, 8:1)
to provide the major isomer 34 as pale yellow oil (80 mg,
30%). Compound 35 was not isolated from the column
2.4.17. (3aR*,4R*,9bS*)-8-Bromo-4-cyano-1,5-dibenzyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline
(37). Methoxyaminal 32 (60 mg, 0.13 mmol) was dissolved
in anhydrous CH2Cl2 (2.6 mL), and TMSCN (51 mg,
0.07 mL, 0.52 mmol) was added dropwise at room tempera-
ture. After stirring at room temperature for 3 h, the reaction
mixture was diluted with CH2Cl2 and quenched with satu-
rated NaHCO3 (2 mL). The organic layer was separated,
washed with H2O and brine, dried (Na2SO4), and concen-
trated. The crude sample was purified by flash chromato-
graphy (hexane/ethyl acetate, 2:1) to provide the title
product 37 (58 mg, 98%) as a colorless solid. Mp: 126–
128 ꢀC. 1H NMR: d¼7.27–7.37 (m, 9H), 7.20–7.24 (m,
3H), 6.76 (d, J¼8.8 Hz, 1H), 4.82 (d, J¼15.2 Hz, 1H),
4.17 (d, J¼15.2 Hz, 1H), 4.06 (d, J¼13.0 Hz, 1H), 4.03 (d,
J¼4.6 Hz, 1H), 3.53 (d, J¼7.8 Hz, 1H), 3.29 (d,
J¼13.0 Hz, 1H), 2.85–2.92 (m, 2H), 2.25 (dd, J¼17.4,
8.6 Hz, 1H), 2.02–2.10 (m, 1H), 1.75–1.81 (m, 1H); 13C
NMR: d¼144.1, 139.2, 136.2, 133.6, 131.7, 129.0, 128.6,
128.3, 128.04, 128.00, 127.1, 126.6, 118.2, 116.2, 112.2,
61.9, 57.4, 53.9, 53.8, 51.4, 42.3, 28.1; IR (neat, cmꢁ1):
3067, 3028, 2970, 2939, 2797. HRMS (m/z): calcd for
MH+ C26H2579BrN3 458.1226, found 458.1213; calcd for
MH+ C26H2581BrN3 460.1206, found 460.1198.
1
due to its instability. Data for 34: H NMR: d¼7.28–7.38
(m, 8H), 7.21–7.26 (m, 2H), 7.24 (d, J¼2.5 Hz, 1H), 7.07
(dd, J¼8.7, 2.5 Hz, 1H), 6.35 (d, J¼8.7 Hz, 1H), 5.69–
5.78 (m, 1H), 4.99–5.06 (m, 2H), 4.56 (d, J¼16.0 Hz, 1H),
4.23 (d, J¼16.0 Hz, 1H), 4.01 (d, J¼12.8 Hz, 1H), 3.64 (d,
J¼8.5 Hz, 1H), 3.54 (d, J¼12.8 Hz, 1H), 3.21 (ddd,
J¼8.7, 5.3, 2.3 Hz, 1H), 2.93 (ddd, J¼9.6, 7.6, 3.7 Hz,
1H), 2.67 (ddd, J¼17.1, 8.7, 2.3 Hz, 1H), 2.36 (ddd,
J¼9.6, 8.9, 7.1 Hz, 1H), 2.28–2.33 (m, 1H), 2.06–2.12 (m,
1H), 1.90–1.98 (m, 2H); 13C NMR: d¼144.3, 140.0, 138.6,
135.4, 132.5, 130.6, 129.0, 128.7, 128.4, 128.2, 127.2,
127.1, 127.0, 117.7, 114.9, 109.4, 63.1, 60.6, 59.4, 54.5,
52.3, 41.1, 35.9, 29.6; IR (neat, cmꢁ1): 3062, 3028, 2928,
2795, 1591; EIMS (m/z): 474.1 (M++2, 12.5), 472.0 (M+,
12), 432.5 (100), 282.8 (22). HRMS (m/z): calcd for MH+
C28H3079BrN2 473.1587, found 473.1571; calcd for MH+
C28H3081BrN2 475.1566, found 475.1558.
2.4.18. 1-Benzyl-6-bromo-2-[3-(tert-butyldimethylsilanyl-
oxy)-prop-1-ynyl]-3-(2-benzylaminoethyl)-1,2-dihydro-
quinoline (38). Methoxyaminal 32 (20 mg, 0.043 mmol)
was dissolved in anhydrous CH2Cl2 (0.5 mL), and TMSOTf
(8 mL, 0.04 mmol) was added dropwise at ꢁ78 ꢀC. After
stirring at ꢁ78 ꢀC for 5 min, a copper acetylide solution
(1.3 mL, 0.13 mmol), which was prepared in situ by stirring
the TBS-protected propargyl alcohol 40 (22 mg, 0.13 mmol),
CuCl (13 mg, 0.13 mmol), and NEt3 (18 mL, 0.13 mmol) in
anhydrous CH2Cl2 (1.3 mL) at room temperature for
20 min, was added. The reaction mixture was allowed to
warm up slowly from ꢁ78 ꢀC to room temperature. After
stirring overnight, the reaction mixture was diluted with
CH2Cl2 and washed with saturated NaHCO3, H2O, and brine,
dried (Na2SO4), and concentrated. The crude product was
purified by flash chromatography (hexane/ethyl acetate,
2.4.15. 1,5-Dibenzyl-8-bromo-2,3,5,9b-tetrahydro-
1H-pyrrolo[3,2-c]quinoline (35). Following the above
representative procedure, methoxyaminal 32 (72 mg,
0.16 mmol), allyltrimethylsilane (0.25 mL, 1.56 mmol),
MeAlCl2 (1 M in hexanes, 0.62 mL, 0.62 mmol), and anhy-
drous CH3CN (3.1 mL) were used. After work-up, 35
1
(w71 mg, >85% based on H NMR) was obtained, which
was not very stable and after trituration with Et2O and expo-
sure to air, slowly converted to 36. Data for 35: a brown semi-
solid. 1H NMR: d¼7.36–7.88 (m, 10H), 7.10 (d, J¼2.3 Hz,
1H), 7.04 (dd, J¼8.7, 2.3 Hz, 1H), 6.39 (d, J¼8.7 Hz, 1H),
6.31 (s, 1H), 5.13 (s, 1H), 4.70 (m, 2H), 3.68 (m, 2H), 3.09
(m, 1H), 2.75 (m, 1H), 2.58 (m, 2H); 13C NMR: d¼142.5,
139.8, 137.6, 137.5, 130.4, 129.0, 128.6, 128.5, 128.4,
128.3, 127.1, 127.0, 126.8, 125.1, 118.3, 114.4, 109.6,
80.6, 58.6, 50.4, 49.3, 29.3.
1
2:1) to provide 38 (17 mg, 70%) as brown oil. H NMR:
d¼7.23–7.35 (m, 10H), 7.12 (dd, J¼8.8, 2.4 Hz, 1H), 7.06
(d, J¼2.4 Hz, 1H), 6.49 (d, J¼8.8 Hz, 1H), 6.18 (s, 1H),
4.61 (d, J¼14.7 Hz, 1H), 4.45 (t, J¼1.5 Hz, 1H), 4.22 (d,
J¼1.5 Hz, 2H), 4.19 (d, J¼14.6 Hz, 1H), 3.76 (d,
J¼2.4 Hz, 2H), 2.69–2.79 (m, 2H), 2.35–2.42 (m, 2H),
0.85 (s, 9H), 0.02 (s, 6H); 13C NMR: d¼144.8, 140.3,
136.8, 134.6, 130.6, 129.0, 128.8, 128.5, 128.2, 127.9,
127.7, 127.1, 125.4, 122.0, 114.0, 110.6, 83.5, 81.3, 54.0,
52.2, 51.8, 51.5, 46.7, 34.5, 25.8, 18.3, ꢁ5.1; IR (neat,
cmꢁ1): 3375, 3031, 2957, 2928, 2856, 1651, 1590. HRMS
(m/z): calcd for MH+ C34H4279BrN2OSi 601.2244, found
2.4.16. 1,5-Dibenzyl-8-bromo-2,3-dihydro-1H-pyr-
rolo[3,2-c]quinolinium chloride (36). A brown semi-solid.
1H NMR: d¼9.35 (s, 1H), 8.07 (s, 1H), 7.72 (d, J¼9.3 Hz,

Y. He et al. / Tetrahedron 62 (2006) 8755–8769
8767
601.2236; calcd for MH+ C34H4281BrN2OSi 603.2224, found
603.2225.
was washed with 2 N HCl (10 mL), water (10 mL), and brine
(10 mL). The organic layer was separated, dried (Na2SO4),
and concentrated. The crude product, which can be directly
used in the next step without further purification, was puri-
fied by flash chromatography (hexane/ethyl acetate, 3:1) to
provide the corresponding N-(benzyloxycarbonyl)propar-
gylamine (1.64 g, 72%) as a colorless solid. Mp: 39–
2.4.19. 1-Benzyl-3-(2-benzylaminoethyl)-6-bromoquino-
linium triflate (39). To a stirred solution of methoxyaminal
32 (20 mg, 0.044 mmol) in anhydrous CH2Cl2 (0.9 mL) was
added dropwise a solution of TMSOTf (16 mL, 0.089 mmol)
in anhydrous at ꢁ78 ꢀC. The reaction mixture was allowed
to warm to room temperature slowly and stirred for 5 h.
Then it was diluted with CH2Cl2, washed by saturated
NaHCO3 and brine (2ꢂ), dried (CaCl2), and concentrated
to provide the title compound 38 (w18 mg, ca. 90%) as
1
41 ꢀC. (lit.41 mp: 35–36 ꢀC). H NMR: d¼7.30–7.37 (m,
5H), 5.12 (s, 2H), 5.08 (br s, 1H), 3.98 (d, J¼2.4 Hz, 2H),
2.25 (t, J¼2.4 Hz, 1H); 13C NMR: d¼156.0, 136.3, 128.7,
128.34, 128.30, 79.8, 71.7, 67.2, 30.9. N-(Benzyloxycarbo-
nyl)propargylamine (500 mg, 2.64 mmol) and di-tert-
butyl-dicarbonate (700 mg, 3.20 mmol) were dissolved in
anhydrous CH3CN (5 mL) at room temperature, then
DMAP (20 mg, 0.16 mmol) was added. After stirring at
room temperature for 4 h, the reaction mixture was diluted
with CH2Cl2, washed with saturated NaHCO3 solution,
H2O, and brine, dried (Na2SO4), and concentrated. The
crude sample was purified by chromatography (hexane/ethyl
acetate, 2:1) to provide the title product 42 (688 mg, 90%) as
1
pale yellow oil. H NMR: d¼10.29 (s, 1H), 8.85 (s, 1H),
8.25 (s, 1H), 8.14 (d, J¼9.5 Hz, 1H), 7.95 (d, J¼9.5 Hz,
1H), 7.39–7.42 (m, 2H), 7.20–7.38 (m, 8H), 6.35 (s, 1H),
3.93 (s, 2H), 3.48 (m, 2H), 3.25 (m, 2H); 13C NMR:
d¼152.5, 146.4, 138.2, 135.7, 135.0, 133.8, 132.6, 132.3,
131.1, 129.9, 129.6, 129.5, 128.8, 128.5, 127.5, 124.5,
120.6, 61.8, 52.4, 47.0, 30.5, 29.9.
1
2.5. General procedure for CuBr mediated reactions
with sonication
a colorless oil. H NMR: d¼7.38–7.41 (m, 2H), 7.30–7.37
(m, 3H), 5.25 (s, 2H), 4.41 (d, J¼2.4 Hz, 2H), 2.20 (t,
J¼2.4 Hz, 1H), 1.48 (s, 9H); 13C NMR: d¼153.1, 151.1,
135.4, 128.6, 128.5, 128.3, 83.7, 79.3, 71.2, 68.8, 36.1,
28.0; IR (neat, cmꢁ1): 3309, 3067, 3036, 2982, 2935,
1797, 1762, 1729, 1696. ESIMS (m/z): 328 (M+K+, 2),
312 (M+Na+, 100), 256 (15), 212 (16).
2.5.1. (3aR*,4R*,9bS*)-8-Bromo-1,5-dibenzyl-
2,3,3a,4,5,9b-hexahydro-4-[3-(tert-butyldimethylsilyl-
oxy)-prop-1-ynyl]-1H-pyrrolo[3,2-c]quinoline (41).
Aminal 31 (50 mg, 0.11 mmol) and the TBS-protected prop-
argyl alcohol 40 (57 mg, 0.33 mmol) were mixed efficiently
in a test tube. Then CuBr (48 mg, 0.33 mmol) was added
followed by addition of water (1 mL) and mixed by efficient
magnetic stirring. Then the test tube was sonicated for 3 h
under N2 protection in a darkened hood. During the course
of the reaction, the water bath was warmed up to w40–
45 ꢀC under sonication. After cooling to room temperature,
the reaction mixture was partitioned between CH2Cl2 and
10% aqueous NH3 solution. The organic layer was separated
and further washed with 10% NH3 solution, H2O, and brine,
dried (Na2SO4), and concentrated. The crude oil was purified
by column chromatography (hexanes/ethyl acetate, gradient
elution, 10:1 to 1:1) to provide product 41 (32 mg, 48%) as
a colorless oil and fragmentation product 38 (27 mg, 40%)
2.5.3. (3aR*,4R*,9bS*)-4-[3-(Benzyloxycarbonyl-tert-bu-
tyloxycarbonylamino)prop-1-ynyl]-8-bromo-1,5-dibenz-
yl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline
(43). Following the general sonication procedure, aminal 31
(50 mg, 0.11 mmol), propargylamine 42 (95 mg, 0.33 mmol)
1
and CuBr (48 mg, 0.33 mmol) were used. H NMR of the
crude reaction mixture indicated that the required adduct
and the fragmentation product were formed in the ratio of
0.6:1. Chromatographic purification (hexane/ethyl acetate,
6:1 to 1:1) of the crude product provided the title compound
43 (25 mg, 32%) as colorless oil. The pure byproduct 44 was
not obtained from the column due to the contamination with
1
unreacted 42. H NMR: d¼7.21–7.38 (m, 15H), 7.18 (d,
1
as a brown oil. H NMR: d¼7.22–7.35 (m, 10H), 7.21 (d,
J¼2.4 Hz, 1H), 7.12 (dd, J¼8.8, 2.4 Hz, 1H), 6.52 (d,
J¼8.8 Hz, 1H), 5.18 (s, 2H), 4.75 (d, J¼16.1 Hz, 1H), 4.40
(d, J¼16.1 Hz, 1H), 4.35 (d, J¼1.7 Hz, 2H), 4.15 (d,
J¼13.0 Hz, 1H), 4.09 (dt, J¼7.1, 1.7 Hz, 1H), 3.38 (d,
J¼6.3 Hz, 1H), 3.25 (d, J¼13.0 Hz, 1H), 2.87 (ddd, J¼9.0,
9.0, 3.7 Hz), 2.52 (m, 1H), 2.21 (ddd, J¼8.8, 8.8, 8.3 Hz,
1H), 1.99 (m, 1H), 1.81 (m, 1H), 1.44 (s, 9H); 13C NMR:
d¼153.0, 151.0, 144.6, 139.9, 138.2, 135.5, 133.6, 131.1,
128.65, 128.62, 128.55, 128.4, 128.2, 127.3, 127.1, 126.9,
124.9, 115.4, 109.3, 83.5, 81.7, 79.9, 68.6, 62.5, 57.6, 53.3,
53.1, 51.2, 42.4, 36.4, 28.0, 27.6; IR (neat, cmꢁ1): 3089,
3065, 3032, 2982, 2934, 2885, 2850, 2801, 1796, 1757,
1725, 1697. HRMS (m/z): calcd for MH+ C41H4379BrN3O4
720.2431, found 720.2424; calcd for MH+ C41H4381BrN3O4
722.2411, found 720.2422.
J¼2.2 Hz, 1H), 7.14 (dd, J¼8.8, 2.2 Hz, 1H), 6.54 (d, J¼
8.8 Hz, 1H), 4.78 (d, J¼16.1 Hz, 1H), 4.42 (d, J¼16.1 Hz,
1H), 4.23 (d, J¼1.5 Hz, 2H), 4.16 (d, J¼13.0 Hz, 1H), 4.12
(dt, J¼6.6, 1.5 Hz, 1H), 3.45 (d, J¼6.6 Hz, 1H), 3.29 (d,
J¼13.0 Hz, 1H), 2.90 (ddd, J¼9.0, 8.8, 3.4 Hz), 2.62 (m,
1H), 2.24 (ddd, J¼8.8, 8.8, 8.8 Hz, 1H), 2.04 (m, 1H), 1.88
(m, 1H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR: d¼144.7,
139.9, 138.3, 133.5, 131.1, 128.65, 128.61, 128.2, 127.3,
127.1, 126.9, 125.3, 115.4, 109.4, 83.7, 82.9, 62.5, 57.8, 53.6,
53.4, 51.8, 51.3, 42.7, 27.8, 25.9, 18.3, ꢁ5.1; IR (neat, cmꢁ1):
3064, 3030, 2958, 2929, 2857. HRMS (m/z): calcd for
MH+ C34H4279BrN2OSi 601.2244, found 601.2227; calcd
for MH+ C34H4281BrN2OSi 603.2224, found 603.2222.
2.5.2. N-(Benzyloxycarbonyl)-N-(tert-butyloxycarbonyl)-
propargylamine (42). To a stirred solution of N-(benzyl-
oxycarbonyloxy)succinimide (3.00 g, 12.0 mmol) in
anhydrous CH2Cl2 (30 mL) was added dropwise propargyl-
amine (0.80 mL, 12.5 mmol) at 0 ꢀC. The reaction mixture
was stirred at 0 ꢀC for 30 min and then overnight at room
temperature. On completion of the reaction, the mixture
2.5.4. Methyl (3aR*,4S*,9bS*)-1,5-dibenzyl-4-methoxy-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-
8-carboxylate (45). To Methoxyaminal 32 (200 mg,
0.43 mmol) in anhydrous THF (4.5 mL) at ꢁ78 ꢀC was
added n-BuLi (1.6 M solution in hexane, 0.28 mL,
0.45 mmol) and stirred for 15 min at ꢁ78 ꢀC. Dimethyl

8768
Y. He et al. / Tetrahedron 62 (2006) 8755–8769
carbonate (0.09 mL, 1.08 mmol) was added dropwise and
stirred for 3 h while the reaction temperature was allowed
to warm up slowly to 0 ꢀC. The reaction was quenched by
careful addition of saturated NH4Cl solution (15 mL) and
the aqueous layer was extracted with CH2Cl2 (3ꢂ). The com-
bined organics were dried (Na2SO4) and concentrated. Ether
was added to the crude oily product, removed by rotary
evaporation, and then dried under high vacuum overnight
with Et2O to provide the oily compound 48 as the hydrochlo-
H
1
ride salt (15 mg, >90% pure by H NMR analysis).43 1
NMR (CD3OD): d¼7.98 (s, 1H), 7.74 (d, J¼8.0 Hz, 1H),
6.83 (d, J¼8.0 Hz, 1H), 4.65 (br s, 1H), 3.81 (s, 3H),
3.34–3.42 (br s, 2H), 3.10 (br s, 1H), 2.99 (br s, 2H), 2.39–
2.50 (br s, 2H), 2.12–2.20 (br s, 1H), 1.80–1.95 (br s, 3H),
1.70 (br s, 1H); 13C NMR (CD3OD): d¼168.3, 151.0,
133.9, 132.6, 119.2, 115.7, 113.3, 59.3, 52.3, 50.8, 43.9,
41.1, 39.4, 30.5, 28.2, 24.0; ESIMS (m/z): 290 (M+H+,
100), 273 (75), 256 (22).
1
to provide 45 (189 mg, greater than 90% pure by H NMR
analysis) as a brown semi-solid, which was directly used in
the next step without further purification. 1H NMR: d¼7.89
(d, J¼2.2 Hz, 1H), 7.76 (dd, J¼8.6, 2.2 Hz, 1H), 7.39–7.41
(m, 2H), 7.20–7.34 (m, 8H), 6.65 (d, J¼8.6 Hz, 1H), 4.92
(d, J¼16.4 Hz, 1H), 4.60 (d, J¼16.4 Hz, 1H), 4.47 (d,
J¼2.9 Hz, 1H), 4.08 (d, J¼13.0 Hz, 1H), 3.83 (s, 3H), 3.66
(d, J¼8.1 Hz, 1H), 3.37 (d, J¼13.0 Hz, 1H), 3.27 (s, 3H),
2.95 (m, 1H), 2.90 (ddd, J¼16.1, 8.1, 2.7 Hz), 2.32 (ddd,
J¼9.3, 9.0, 7.6 Hz), 2.08 (m, 1H), 1.83 (ddd, J¼16.1, 12.2,
8.1 Hz); 13C NMR: d¼167.4, 147.9, 140.1, 138.0, 131.7,
130.4, 128.7, 128.2, 127.2, 127.0, 126.9, 125.4, 119.7,
113.0, 94.3, 62.0, 58.6, 54.9, 54.0, 51.79, 51.71, 51.67,
42.4, 28.2; IR (neat, cmꢁ1): 3062, 3028, 2963, 2930, 2850,
2824, 1711, 1609. ESIMS (m/z): 465 (M+Na+, 1), 443
(M+H+, 5), 411 (100), 353 (15).
2.6. X-ray data collection, solution, and refinement of
the structures cis-26 and trans-26
A suitable crystal was selected and attached to a glass fiber
using 5 min epoxy-glue and immediately placed in the path
of the X-ray beam. Data collections for compounds cis-26
and trans-26 were carried out on a Siemens P4 diffractome-
ter equipped with a LT-2A device for low-temperature work
and graphite monochromated Mo Ka radiation (l¼0.710
˚
73 A). Data were collected at the room temperature. All
the structures were solved and refined using the Bruker
SHELXTL software package. Compound cis-26 crystallizes
ꢀ
in the triclinic P1 space group with two chemically similar,
but crystallographically different molecules in the asymmet-
ric unit. trans-26 Crystallizes in the monoclinic P2(1)/n
space group. Crystallographic data (cif files) for cis-26 and
trans-26 have been deposited at the Cambridge Crystal-
lographic Data Center, CCDS nos. 287965 and 287966.
Copies of this information may be obtained free of charge
from the Director, Cambridge Crystallographic Data Centre
(CCDC), 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk
or http://www.ccdc.cam.ac.uk).
2.5.5. Methyl (3aR*,4R*,9bS*)-4-[3-(benzyloxycarbonyl-
tert-butyloxycarbonylamino)-prop-1-ynyl]-1,5-dibenzyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-
8-carboxylate (47). Following the general sonication proce-
dure, crude methyl ester 45 obtained directly from last step
(100 mg, w0.22 mmol), 42 (195 mg, 0.66 mmol) and CuBr
(97 mg, 0.66 mmol) were used. Chromatography (hexanes/
EtOAc, 6:1 to 1:1) of the crude oil provided product 47
(63 mg, 40% for two steps) as colorless oil. The pure frag-
mentation byproduct was not obtained from the column
due to the contamination with unreacted 42. 1H NMR:
d¼7.78 (d, J¼2.0 Hz, 1H), 7.74 (dd, J¼8.8, 2.0 Hz, 1H),
7.26–7.37 (m, 8H), 7.18–7.25 (m, 7H), 6.67 (d, J¼8.8 Hz,
1H), 5.18 (s, 2H), 4.93 (d, J¼16.9 Hz, 1H), 4.69 (d, J¼
16.9 Hz, 1H), 4.37 (d, J¼1.5 Hz, 2H), 4.28 (dt, J¼8.8,
1.5 Hz, 1H), 4.21 (d, J¼13.0 Hz, 1H), 3.83 (s, 3H), 3.36 (d,
J¼5.1 Hz, 1H), 3.20 (d, J¼13.0 Hz, 1H), 2.89 (ddd, J¼9.0,
9.0, 3.7 Hz), 2.45 (m, 1H), 2.19 (ddd, J¼9.8, 9.5, 7.1 Hz,
1H), 2.04 (m, 1H), 1.78 (m, 1H), 1.45 (s, 9H); 13C NMR:
d¼167.3, 153.0, 151.1, 149.0, 140.0, 137.8, 135.4, 133.6,
130.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 127.1,
127.0, 126.8, 120.4, 117.9, 112.6, 83.6, 81.6, 80.6, 68.7,
63.0, 57.0, 53.0, 52.3, 51.7, 50.8, 41.5, 36.4, 28.0, 27.1; IR
(neat, cmꢁ1): 3062, 3006, 3030, 2979, 2945, 2796, 1794,
1756, 1711, 1610. HRMS (m/z): calcd for MH+
C43H46N3O6 700.3381, found 700.3380.
Acknowledgements
This work has been supported by The Robert A. Welch Foun-
dation (C.J.L.: Grant Y-1362 and H.V.R.D.: Grant Y-1289)
and the University of Texas at Arlington (Research Enhance-
ment Program). The preliminary experimental contributions
of Ashok Viswinathan, Judson Severson, and Brian Wayland
are greatly appreciated. The NSF is thanked for the provision
of funding for the purchase of NMR spectrometers (CHE-
9601771 and CHE-0234811) employed in this project.
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