Stereocontrolled conjugate additions to dihydroindolizinone systems. Synthesis of enantiopure polysubstituted tetrahydropyrrolo[2,1-a]isoquinolones

Article abstract of DOI:10.1016/j.tet.2009.05.011

Conjugate addition reactions of various types of nucleophiles to the γ-lactam unit of dihydroindolizinone systems have been studied. The addition of cuprates, amines or stabilized carbanions requires the activation of the unsaturated bicyclic lactam with

Full text of DOI:10.1016/j.tet.2009.05.011

Tetrahedron 65 (2009) 5787–5798
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Stereocontrolled conjugate additions to dihydroindolizinone systems. Synthesis
of enantiopure polysubstituted tetrahydropyrrolo[2,1-a]isoquinolones
´
´
´
Cristina Camarero, Ines Gonzalez-Temprano, Asier Gomez-SanJuan, Sonia Arrasate,
*
Esther Lete , Nuria Sotomayor
´
´
´
´
Departamento de Quımica Organica II, Facultad de Ciencia y Tecnologıa, Universidad del Paıs Vasco, Euskal Herriko Unibertsitatea, Apdo. 644, 48080 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Conjugate addition reactions of various types of nucleophiles to the g-lactam unit of dihydroindolizinone
Received 30 March 2009
Received in revised form 5 May 2009
Accepted 6 May 2009
systems have been studied. The addition of cuprates, amines or stabilized carbanions requires the ac-
tivation of the unsaturated bicyclic lactam with a EWG at C-2, while sulfur-stabilized carbanions are
reactive enough to add to the unsubstituted lactam. The stereochemical outcome of the conjugate ad-
dition reaction depends on the nature of the substituent at the angular position, and the incoming
nucleophile. Thus 1,10b-cis or 1,10b-trans diastereomers could be obtained selectively with dr>95:5. The
tandem conjugate addition–alkylation also takes place in good yields. These reactions have been applied
to the synthesis of enantiopure tetrahydropyrrolo[2,1-a]isoquinolines.
Available online 9 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
sulfur-stabilized anions are used as nucleophiles.12 Thus, in the case
of
a
,
b
-unsaturated
g
-lactams, we have recently described a stereo-
Pyrrolo[2,1-a]isoquinolines1 have drawn a lot of interest in the
last years due to their potential role in therapeutics for the central
nervous system related disorders. This is attributed to their dual H3
antagonist/serotonin transporters inhibitor activity.2 Because of
their biological activity, these alkaloids are also regarded as
promising muscarinic agonist,3 antiplatelet,4 and antitumor5
agents. The importance of these nitrogen heterocycles is further
enhanced by their utility as advanced key intermediates for the
synthesis of more complex alkaloids.6 For several years we have
dedicated part of our research program to the development of new
methods for the synthesis of nitrogen heterocycles, based on dia-
controlled 1,4-addition of
a-lithiodithioacetals to tetrahydro-
benzo[a]quinolizines, which led to the synthesis of emetine-like
derivatives.13 On the other hand, the introduction of a carbomethoxy
group in the a-position of a,b-unsaturated oxazolopiperidone lac-
tams has allowed Amat et al.14 to achieve the conjugate addition of
hardnucleophilestogenerate3,4-and2,4-disubstitutedenantiopure
piperidines, including the antidepressant drug (ꢀ)-paroxetine, cis-
fused perhydrocycloalka[c]pyridines, and the indole alkaloid
(þ)-uleine.15 The latter strategy has been proven to be effective for
the conjugate addition of organocuprates to five-member a,b-un-
saturated lactams, as it has been illustrated in the synthesis of
stereoselective Parham cyclization,7 and intramolecular
a-amido-
erythrinanes.16
alkylation reactions.8 Through this effort we were able to achieve
a stereodivergent approach for synthesis of the enantiopure C-10b
substituted 5,6-dihydropyrroloisoquinolones.9 The presence of the
a,b-unsaturated lactam unit in benzo-fused indolizinones would
allow for possible further functionalization to more complex tar-
gets via conjugate addition reactions. In fact, conjugate 1,4-addition
In our continued interest in the conjugate addition reactions on
the a,b-unsaturated bicyclic lactams, we investigated the conjugate
additions of different types of nucleophiles (organocuprates,
amines, .) to dihydroindolizinones (Fig. 1), paying special atten-
tion to the effect of both the nucleophile and the substitution on
C-10b (R1¼Me, n-Bu) on the stereoselectivity. To show the synthetic
potential of these conjugate additions, the reactions were applied
to the synthesis of enantiopure polyfunctionalized pyrrolo[2,1-
a]isoquinolines.17
of organometallic reagents to a,b-unsaturated carbonyl compounds
is one of the most useful methods to assemble carbon–carbon
bonds in organic chemistry.10
It is known that a,b-unsaturated amides and lactams without an
additional withdrawing group in the
a-position possess an in-
herently low reactivity in 1,4-addition reactions,11 except when
2. Results
Some years ago we reported the conjugate addition reactions of
a
-lithiodithioacetals (2-lithio-1,3-dithiane and bis(phenylthio)-
* Corresponding author. Tel.: þ34 94 6012576; fax: þ34 94 6012748.
E-mail address: esther.lete@ehu.es (E. Lete).
methyllithium) to racemic unsaturated bicyclic -lactams 1a and
g
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.011

5788
C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
a,b
N
N
N
N
O
O
E
*
*
O
O
R1
R1
R1
R1
E+
* *
R3
R2
CO2Bn
3a, R1 = CH3
3b, R1 = n-Bu
4a, R1 = CH3 (61%)
4b, R1 = n-Bu (75%)
Nu-
R1: Me, n-Bu
R3: EWG, H
c
Table 1
CH3O
CH3O
Nu: , R2Li, R22Li/CuI, (R4S)2CHLi, etc
E: H, Et
CH3O
CH3O
Figure 1.
+
O
N
N
O
R1
R2
R1
R2
1b. Thus, lactams 1a,b underwent a clean 1,4-addition reaction of 2-
lithio-1,3-dithiane with complete regio- and stereoselectivity in 1 h
at room temperature to provide the corresponding 1,10b-cis iso-
mers. Interestingly, a reversal of the stereoselectivity was observed
when the C-10b butyl substituted lactam 1b was reacted with
bis(phenylthio)methyllithium, obtaining the trans adduct, as
a single diastereomer in high yield.18 It was necessary to show that
these diastereoselective conjugate addition reactions could be used
for the synthesis of enantiomerically pure compounds. In this
context, we have previously described the synthesis of the enan-
tiopure C-10b substituted 5,6-dihydropyrroloisoquinolones 1a,b.9b
Thus, addition of 2-lithio-1,3-dithiane and bis(phenylthio)
methyllithium prepared by treatment of the corresponding dithio-
acetals with n-BuLi at ꢀ78 ꢁC, to these lactams (10bR)-1a,b afforded
pyrroloisoquinolines (1R,10bR)-2a and (1S,10bR)-2b, respectively,
with complete stereocontrol (Scheme 1). The enantiomeric purity (ee
>99%) of adducts was established by comparison with the corre-
sponding racemates by CSP HPLC.
Consistent with the low reactivity of unsaturated lactams and
amides, we found that 1a,b did not react with organocuprates,
enolates, and nitrogen nucleophiles. For instance, conjugate addi-
tion reactions of organocuprates were tested on 1a. Thus, several
experiments were carried out varying temperature (from ꢀ78 ꢁC to
rt), reaction time (3–48 h) or using additives (HMPA or Lewis acids,
such as TMSCl). However, unreacted lactam 1a was always re-
covered. In the case of the addition of enolates to 1a, no reaction
occurred with preformed enolates derived from cyanoacetate,
malonate, and acetoacetate, even working under reflux. In a similar
way, screening of several experimental conditions for the addition
of amines and lithium amides led to identical results.
CO2R3
(1SR,2SR,10bSR)-5
CO2R3
(1RS,2RS,10bSR)-6
Scheme 2. Reagents and conditions: (a) LDA (2 equiv), ꢀ78 ꢁC, 1 h, THF; ClCO2Bn
(1 equiv), ꢀ78 ꢁC, 1 h; PhSeBr (1 equiv), ꢀ78 ꢁC, 1 h, (b) H2O2, pyridine, 0 ꢁC to rt,
CH2Cl2. (c) (R2)2CuLi, THF, ꢀ78 ꢁC to rt, 16 h.
was assembled through
a-amidoalkylation reactions of N-(3,4-
dimethoxyphenethyl)-succinimide, a procedure that has been suc-
cessfully used to access various types of isoquinoline skeletons.19
Thus, a double bond was introduced on 3a,b19a in high yield by
an oxidative elimination of a selenoxide. Subsequent sequential
treatment with LDA, benzyl chloroformate, and phenylselenyl
bromide, followed by elimination with H2O2 provided the dihy-
dropyrroloisoquinolones 4a,b, as described in Scheme 2.
We first studied the addition of Gilman’s cuprates, prepared by
addition of 2 equiv of methyllithium or n-butyllithium to a sus-
pension of CuI (1 equiv) in THF at 0 ꢁC. However, it was necessary to
stir the reaction mixture at room temperature overnight, after
adding the substrates 4a,b, to have good conversions. In the 1,4-
addition reaction of both organocuprates to lactam 4a (R1¼Me) the
cis adducts were obtained as single diastereomers, while the re-
actions took place with reasonable diastereoselectivities, also in
favor of the cis diastereomer, when the lactam 4b (R1¼n-Bu) was
used as substrate (Table 1).
Since it is known that the use of low order cyanocuprates can
improve the stereoselectivity of conjugate addition reactions,20 we
also tried the addition of MeCuCNLi (Table 1, entry 3) to lactam 4a,
but although the diastereoselectivity was still high in favor of the
cis diastereomer 5a, the yield dropped to 58%. The 1,4-addition of
Bu2CuLi to both lactams gave moderate yields, due to the simul-
taneous formation of the corresponding adducts with a CO2Bu
group, instead of the CO2Bn. Therefore, we prepared the dihydro
derivative 4c, with the CO2Bu group, and test on it the conjugate
addition reaction as can be seen in Table 1, obtaining similar levels
of diastereoselectivity.
Therefore, we decided to introduce an electron withdrawing
a-position to enhance the re-
activity of these lactams. Thus, our first task was to prepare the ac-
group (benzyloxycarbonyl) in the
tivated unsaturated lactams 4a,b. The pyrroloisoquinolone skeleton
CH3O
CH3O
CH3O
CH3O
a
Finally, the alkoxycarbonyl group necessary for the conjugate
addition could be removed by hydrogenolysis or hydrolysis followed
N
N
O
O
CH3
CH3
S
S
Table 1
Conjugate additions of organocuprates to 4a–c
(10bR)-1a
(1R,10bR)-2a (85%, dr >95:<5)
ee>99% [α]23D + 54 (c 0.01, CHCl3)
Entry
Subs
R1
R2
R3
Prod
Yield (%)
dr 5/6
1
2
3
4
5
6
7
4a
4b
4a
4a
4b
4c
4c
CH3
n-Bu
CH3
CH3
CH3
CH3
n-Bu
n-Bu
CH3
Bn
Bn
Bn
Bn
Bn
n-Bu
n-Bu
5a
5b:6b
5a
85
89
58
51b
57c
75
78
>95:<5
67:33
93:7
>95:<5
70:30
61:39
66:34
CH3O
CH3O
CH3O
a
a
CH3
5c
N
N
O
O
CH3O
n-Bu
n-Bu
n-Bu
5d:6d
5e:6e
5f:6f
Bu
Bu
PhS
n-Bu
SPh
a
MeCuCNLi was used as nucleophile.
b
The same pyrroloisoquinoline but with a butoxy-carbonyl group (5c0) was also
(10bR)-1b
(1S,10bR)-2b (65%, dr >95:<5)
ee>99% [α]23D + 79 (c 0.02, CHCl3)
isolated in a 24% yield.
c
The same pyrroloisoquinoline but with a butoxy-carbonyl group (5f) was iso-
Scheme 1. Reagents and conditions: (a) (R2S)2CHLi, ꢀ78 ꢁC to rt, 1 h.
lated in a 15% yield.

C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
5789
Table 2
CH3O
CH3O
Conjugate additions of enolates to 4a,b
a
5a
N
O
Entry
Subs
R1
R2
R3
Prod
Yield (%)
dr 10/11
H3C
H3C
1
2
3
4
5
6
4a
4b
4a
4b
4a
4b
CH3
n-Bu
CH3
n-Bu
CH3
n-Bu
CN
CN
CO2CH3
CO2CH3
CH3CO
CH3CO
CH3
CH3
CH3
CH3
Et
10a
10b
10c:11c
11d
10e:11e
10f:11f
64
>95:<5
>95:<5
20:80
<5:>95
50:50c
50:50
72a
61
(1SR, 10bSR)-7 (44%)
51b
89
CH3O
b
Et
60
6e
N
O
CH3O
a
Conversion: 72%.
Conversion: 90%.
Bu
H3C
b
c
dr was determined from 1H NMR spectra of the mixture.
(1RS, 10bSR)-8 (86%)
moderate to good yields. The best results were obtained by using
preformed enolates, to which a solution of the substrate was added
(Scheme 5). Conjugate addition of enolate of methyl cyanoacetate
proceeded very cleanly in dry THF under reflux in 3–4 h to give the
corresponding cis diastereomers 10a and 10b in good yields and
with complete diastereoselectivity. When the reactions were car-
ried out with enolate of dimethyl malonate reversal of stereo-
selectivity was observed and it was possible to obtain the trans
diastereomers 11c and 11d. However, addition of the enolate of
ethyl acetoacetate took place cleanly in ethanol at room tempera-
ture, but with complete lost of diastereoselectivity (Table 2).
We next examined the conjugate addition reactions of nitrogen
nucleophiles, which could allow us to synthesize the corresponding
1-aminopyrroloisoquinolone-2-carboxylate derivatives. These
types of indolizinone-based amino acid derivatives have gained
considerable attention due to their biological properties.21
Scheme 3. Reagents and conditions: (a) Pd/C, H2, MeOH, rt, 2 days; toluene, reflux,
12 h. (b) NaOH, THF/H2O/MeOH, rt, 18 h; toluene, reflux, 12 h.
by decarboxylation (Scheme 3), obtaining the 1,2-disubstituted
pyrroloisoquinolines 7 and 8, and confirming the stereochemistry of
the precursors 5 and 6. On the other hand, tandem conjugate addi-
tion-a-alkylation reaction is an efficient method to build up more
complex molecules. Thus, the intermediate lithium enolate derived
from the conjugate addition of Gilman’s methyl cuprate to un-
saturated lactam 4a could be trapped with methyl iodide to give the
1,2,2-trisubstituted tetrahydropyrroloisoquinolone as an in-
separable epimeric mixture: 9a and 9a0 in an 86:14 ratio. The same
intermediate can also be trapped in one pot procedure by allyl iodide
to give a mixture of 9b and 9b0 in a similar ratio (80:20). The addition
of (CH3)2CuLi to 4a was again syn selective, though enolate alkylation
was not completely stereoselective (Scheme 4). Therefore, the se-
quential conjugate addition of organocuprates and in situ alkylation
allowed us the construction of quaternary carbon centers.
Michael reaction of amines promoted by Lewis acids or base
catalysts is one of the most important carbon–nitrogen bond-
forming reactions in organic synthesis. Thus, the conjugate addi-
tion of homochiral secondary lithium amides to
a,b-unsaturated
4a
esters and amides has been widely used for the asymmetric syn-
thesis of amino acid derivatives.22 On the other hand, although aza-
Michael reactions of neutral amines often requires the use of Lewis
acids in stoichiometric sub-stoichiometric amounts,23 there are
also examples of reactions carried out with the amines at room
temperature24 or even under ‘green’ reaction conditions, such as
conjugate additions accelerated by water25 or silica gel.26
Thus, we first tried the addition of bulky lithium bis-
(trimethylsilyl)amide. The addition to lactam 4a could be accom-
plished in good yield and complete stereoselectivity, isolating only
the trans diastereomer 12 (rd >95:<5) as shown in Scheme 6. We
next studied the possibility performing the addition of benzyl-
amine without any added base. However, when lactam 4a was
treated with benzylamine under several experimental conditions,
we observed that, prior to 1,4-addition, the carboxylic ester was
transformed into the corresponding amide, and so lactam 4d, with
a CONHBn group, was isolated as the only reaction product when
a,b
CH3O
CH3O
CH3O
CH3O
+
O
N
N
O
H3C
H3C
H3C
H3C
CO2Bn
R3
CO2Bn
R3
(1SR,2RS,10bSR)-9
(1SR,2SR,10bSR)-9'
R3 = CH3, 57%, dr 9a:9a' 86:14
R3 = allyl, 50%, dr 9b:9b' 80:20
Scheme 4. Reagents and conditions: (a) (CH3)2CuLi, THF, ꢀ78 ꢁC to 0 ꢁC, 24 h; (b) R3I,
rt, 24 h.
In order to expand the possibilities of functionalization on C-1 of
the pyrroloisoquinolone skeleton, we studied the addition of vari-
ous enolates to 4a,b. Thus, 4a,b underwent 1,4-additions of eno-
lates derived from cyanoacetates, malonates, and acetoacetates in
CH3O
4a,b
a
4a
N
O
CH3O
CH3
a or b
(TMS)2N
CO2Bn
b
(1RS,2RS,10bSR)-12 (71%)
CH3O
CH3O
CH3O
CH3O
+
N
N
O
O
CH3O
CH3O
R1
R2
R1
R2
CH3O
b
N
CO2Bn
CO2R3
CO2Bn
N
O
CO2R3
O
CH3O
CONHBn
CH3
CH3
(1RS,2SR,10bSR)-10
(1SR,2RS,10bSR)-11
BnHN
CONHBn
Scheme 5. Reagents and conditions: (a) NCCH2CO2Me (1 equiv) or (MeO2C)2CH2
(1 equiv), NaNH2 (1 equiv), DMPU, THF, rt to reflux. (b) CH3COCH2CO2Et (1 equiv),
Ba(OH)2 (1 equiv), EtOH, rt.
4d (98%)
(1SR,2SR,10bSR)-13 (72%)
Scheme 6. Reagents and conditions: (a) LiHMDS, 78 ꢁC to rt. (b) BnNH2, H2O, rt, 18 h.

5790
C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
no NOE
X
no NOE
E
X
Nu
parallel attack
(exo)
CH3O
CH3O
CH3O
CH3O
CH3O
-
O
H1
H1
O
O
N
4a,b
CO2Bn
N
N
CONHBn
H2
CO2Bn
H2
CH3O
Nu
HN
H3C
H3C
H
R
Bn
NC
CO2Me
NOE
NOE
R = H
R = H
Jax-ax = 11.1 Hz
J
ax-ax = 10.3 Hz
CH3O
CH3O
(1RS, 2SR, 10bSR)-10a
(1SR, 2SR, 10bSR)-13
CH3O
CH3O
O
N
E
O
N
Nu
no NOE
X
CO2Bn
no NOE
X
Nu
CO2Bn
NOE
R
NOE
H2
H
CH3O
CH3O
R
H1
O
CH3
CH3O
CH3O
5, 10, 13
9
N
CH3
O
N
Scheme 7. Stereochemical outcome of the addition reactions.
H3C
CO2Bn
X
H3C
H1
CO2Bn
Bu
no NOE
NOE
Jeq-eq = 1.6 Hz
when a bulky bis(trimethylsilyl)amide or malonate derived enolates
are used as nucleophiles, the trans adducts 12 and 11c,d, respectively,
were obtained preferentially. It is also noteworthy that protonation
of the enolate intermediate occurs from the same face of incoming
nucleophile to afford the more stable 1,2-trans adducts. On the
contrary, approach of bulkier electrophiles (E) takes place opposite to
the pseudo-axial R group on C-10b and the nucleophile on C-1,
leading mainly to cis adducts 9. Although there are relatively few
NOE
(1RS, 2RS, 10bSR)-6b
(1SR, 2SR, 10bSR)-9a
Figure 2. Selected NOE enhancements for 10a, 13, 6b, and 9a.
1 equiv of the amine was used. Therefore, we prepared the lactam
4d and test on it the conjugate addition reaction as can be seen in
Scheme 6. The best results were obtained by slowly adding ben-
zylamine (1.8 equiv) to a mixture of the lactam (1 equiv) and water
(5 equiv) without solvent at room temperature and then stirring
the reaction mixture for 18 h, affording the cis adduct 13 in good
yield as a single diastereomer (dr >95:<5).
examples of conjugate addition reactions to bicyclic g
-lactams,20,27
our results are in agreement with Meyers,20,27a,b who has studied the
effect of the angular substituent in the facial selectivity observed in
the conjugate addition of nucleophiles to bicyclic
from pyroglutamic acid. These results are also in agreement with
previous results of our group on bicyclic
-lactams.13 When stabilized
g-lactams derived
d
NOESY and COSY experiments confirmed the stereochemistry of
all the tetrahydropyrroloisoquinoline derivatives. As an example,
the most significant results for pyrroloisoquinolines 6b, 9a,10a, and
13 are shown in Figure 2. Thus, in the 1,10b-cis substituted de-
rivatives 10a or 13, the J value of the spin system formed by H-1 and
H-2 protons indicates that both are in a pseudo-axial position (10–
12 Hz). Besides, NOE difference spectroscopy showed an enhance-
ment between the methyl group in C-10b and H-2. In the case of the
alkylated system 9a, a clear NOE enhancement was observed
between H-1 and the methyl group on C-2, and between both
methyl groups on C-10b and C-1.
On the other hand, for the 1,10b-trans diastereomers as 6b, the J
value of the system formed by H-2 and H-1 protons (1.6 Hz) in-
dicate that both are in a pseudo-equatorial position. In this case, the
absence of NOE enhancement between methyl group on C-1 and
the butyl group on C-10b, confirms that they are in a relative trans
disposition. The rest of the NOE experiments carried out were fully
consistent with the proposed stereochemistry in each case.
We can now propose a general model to rationalize the facial
selectivity (Scheme 7). Thus, attack of the nucleophile to the con-
formationally rigid lactams 4 occurs under stereoelectronic control,
parallel with respect to the substituent at C-10b (exo attack, from
the convex face). This leads to a syn disposition of both substituents
in the resulting enolate intermediate. However, when the size of the
substituent at the angular position increases and/or bulky nucleo-
philes are used, this interaction in the resulting intermediate or in
the transition state leading to it would favor an antiparallel attack
thus leading to the formation of the trans diastereomers in a larger
ratio.
anions are used, the sterochemical outcome of the conjugate addi-
tion could also be attributed to the thermodynamic stability of the
resulting stereomers, although this possibility is unclear, as the ad-
ducts, once formed, do not appear to undergo reversal to the un-
saturated lactam.
As shown above, the conjugate addition of cuprates or enolates
required the presence of an electron withdrawing group on C-2 to
proceed efficiently. Our previously described strategy for the syn-
thesis of enantiomerically pure 5,6-dihydropyrroloisoquinolones as
1a,b9b was based on the stereoselective inter- or intramolecular
a-
amidoalkylation reactions of norborn-5-ene-2,3-dicarboxyimides
that incorporate a 2-exo-hydroxybornylsulfinyl as a chiral auxiliary.
At this point we thought that the sulfinyl group used as a chiral
auxiliary could also act as an electron withdrawing group. In fact,
a,b-unsaturated sulfoxides have been extensively used in asym-
metric synthesis as versatile chiral reagents with the sulfinyl group
playing the role of chiral auxiliary.28 Thus, it has been demon-
strated that the conjugate addition of several types of nucleophiles
to chiral a,b-unsaturated a-arylsulfinyl carbonyl compounds took
place in a completely stereoselective manner.29
First, methaneisoindolin[2,3-a]isoquinolin-8-one 14 was pre-
pared according to our described procedure.9b Then, as shown on
Scheme 8, the double bond was unmasked by a thermal retro-
Diels–Alder reaction. Thus, using a FVP technique (500 ꢁC,1 mmHg)
the
a,b-unsaturated pyrroloisoquinoline (10bR)-15 was obtained
without racemization, although in low yield (20%). This yield could
be significantly improved to 54% performing the extrusion of
cyclopentene in refluxing o-DCB to afford enantiomerically pure
(10bR)-15. The enantiomeric purity of (10bR)-15 was established by
removal of the sulfinyl group with SmI2 and t-BuOH/HMPA to
afford 7. The sulfinyl group incorporated on C-2 turned out to be
able to activate the lactam toward conjugate addition reactions.
Thus, as shown on Scheme 7, attack of the nucleophiles to
substituted lactams 4 occurs mainly parallel to the substituent at
C-10b to afford 1,-10b-cis pyrroloisoquinolines 5, 10, and 13. Only

C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
5791
CH3O
CH3O
CH3O
CH3O
temperature for 1 h, and allowed to warm up to rt. A solution of
pyrroloisoquinolone (10bR)-1a9b (27 mg, 0.1 mmol) in THF (3 mL)
was added, and the resulting solution was stirred for 24 h. The
reaction was quenched by the addition of saturated NH4Cl (5 mL).
The organic layer was separated and the aqueous phase was
extracted with Et2O (3ꢂ10 mL). The combined organic extracts
were washed with 10% aq NaOH (2ꢂ10 mL), brine (2ꢂ10 mL), and
H2O (2ꢂ10 mL), then dried (Na2SO4) and concentrated in vacuo.
Flash column chromatography (silica gel, 80% hexane/AcOEt)
afforded pyrroloisoquinolone (1R,10bR)-2a, (34 mg, 85%) as an oil:
a
N
N
O
O
H3C
H
H3C
S R*
O
R*
S
O
14
(10bR)-15 (54%)
[α]23D + 99.8 (c 0.5, CHCl3)
OH
R*=
b
CH3O
CH3O
CH3O
CH3O
mp (Et2O) 155–156 ꢁC. IR (KBr)
CDCl3):
n
.
¼1684 cmꢀ1 1H NMR (300 MHz,
c
N
N
O
O
d
¼1.67 (s, 3H), 1.67–1.94 (m, 1H), 2.09–2.25 (m, 1H), 2.48–
H3C
H3C
H3C
H3C
2.62 (m, 2H), 2.71 (dtd, J¼8.5, 8.3, 3.5 Hz, 1H), 2.82–3.06 (m, 7H),
3.84 (s, 3H), 3.89 (s, 3H), 4.25 (dd, J¼12.3, 5.5 Hz, 1H), 4.62 (d,
J¼3.5 Hz,1H), 6.54 (s, 1H), 6.93 (s, 1H). 13C NMR (75.47 MHz, CDCl3):
R*
S
O
(1R,10bR)-7 (56%)
(1R, 2R,10bR)-16 (56%)
[α]23D + 131.3 (c 0.5, CHCl3)
d
¼23.6, 25.2, 28.0, 30.4, 31.7, 33.9, 34.8, 48.6, 49.3, 55.8, 56.2, 64.2,
ee>99%
108.5, 111.8, 125.5, 134.1, 147.5, 147.8, 171.5. LRMS (EI, 70 eV): m/z
(%)¼380 (Mþþ1, 5), 379 (Mþ, 15), 364 (27), 272 (8), 258 (12), 207
(10), 206 (64), 205 (17), 204 (13), 190 (12), 121 (11), 120 (10), 119
[α]23D + 109 (c 0.1, CHCl3)
Scheme 8. Reagents and conditions: (a) o-DCB, reflux, 24 h. (b) MeMgCl, CuI, TMSCl,
ꢁC, 16 h. (c) SmI2, HMPA, t-BuOH, rt, 2 h.
0
(100), 85 (10), 83 (10), 71 (12), 57 (14), 55 (11). C19H25NO3S2: calcd C
23
60.12, H 6.64, N 3.69; found: C 59.91; H 6.76; N 3.48. [
a
]
þ54.0 (c
D
After some experimentation, we found that best results were
obtained using the cuprates, generated by treatment of MeMgCl
with CuI, in the presence of TMSCl. Thus, (1R,10bR)-16 was obtained
in moderate yield as a single diastereomer. The addition of Gilman’s
cuprates under the conditions described on Table 1 led to slightly
lower yields. Therefore, the sulfinyl group plays a dual role, both as
chiral auxiliary in the synthesis of 14 and as activating group for the
conjugate addition. The stereochemical outcome is the same that
has been observed with 4a, so it seems that in this case it should be
controlled by the axial substituent on C-10b, and not by the sulfinyl
group. Finally, reductive removal of the sulfinyl group with SmI2
provided (1R,10bR)-pyrroloisoquinoline 7 in enantiomerically pure
form. The enantiomeric purity (ee>99%) of adducts was established
by comparison with the corresponding racemates by CSP HPLC.
0.01, CHCl3). The enantiomeric excess determined by CSP HPLC was
>99% by comparison with the racemic mixture. Chiralcel OD, 5%
hexane/2-propanol, 0.4 mL/min; t [(1R,10bR)-2a]¼25 min (>99%);
tR[(1S,10bS)-2a]¼19.9 min (<1%).
4.2. (1S,10bR)-(D)-1-Butyl-2-[bis(thiophenyl)methyl]-8,9-
dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3-one (2b)
To a solution of bis(thiophenyl)methane (134 mg, 0.56 mmol) in
dry THF (5 mL), n-BuLi (0.3 mL of a 1.4 M solution in hexanes,
0.42 mmol) was added at ꢀ78 ꢁC. The resulting mixture was stirred
at this temperature for 1 h, and allowed to warm up to rt. A solution
of pyrroloisoquinolone (10bR)-1b (84 mg, 0.28 mmol)4 in THF
(5 mL) was added, and the resulting solution was stirred for 24 h.
The reaction was quenched by the addition of saturated NH4Cl
(10 mL). The organic layer was separated and the aqueous phase
was extracted with Et2O (3ꢂ15 mL). The combined organic extracts
were washed with 10% aq NaOH (2ꢂ15 mL), brine (2ꢂ15 mL), and
H2O (2ꢂ15 mL), then dried (Na2SO4) and concentrated in vacuo.
Flash column chromatography (silica gel, 80% hexane/AcOEt)
afforded pyrroloisoquinolone (1S,10bR)-2b, (97 mg, 65%) as an oil:
3. Conclusion
In conclusion, conjugate addition reactions of various types of
nucleophiles to the g-lactam unit of 5,6-dihydropyrrolo[2,1-a]iso-
quinolines allows the stereocontrolled formation of carbon–carbon
bonds at the C-1 position. While sulfur-stabilized anions react with
non-activated lactams, the addition of other nucleophiles as cup-
rates, amines or p-stabilized carbanions requires the presence of an
mp (Et2O) 118–119 ꢁC; IR (KBr)
CDCl3):
2H), 2.51–2.56 (m, 1H), 2.81–2.90 (m, 3H), 3.01–3.15 (m, 2H), 3.66
(s, 3H), 3.82 (s, 3H), 4.28 (d, J¼2.1 Hz, 1H), 4.42–4.48 (m, 1H), 6.19 (s,
1H), 6.51 (s, 1H), 6.68–6.72 (m, 2H), 7.06–7.29 (m, 8H). 13C NMR
n
¼1684 cmꢀ1
.
1H NMR (300 MHz,
electron withdrawing group on C-2. The attack of the nucleophile
occurs preferentially parallel to the substituent on C-10b, although
the steric interaction between the angular substituent on C-10b and
the incoming nucleophile may cause a reversal of the stereo-
chemical course of the addition. Thus 1,10b-cis or 1,10b-trans di-
astereomers could be selectively obtained. These reactions proceed
with complete stereocontrol on chiral non-racemic substrates,
allowing the synthesis of enantiomerically pure 1,10b-disubstituted
tetrahydropyrrolo[2,1-a]isoquinolines. Thus, the 2-exo-hydroxy-
bornylsulfinyl group plays a dual role, as a chiral auxiliary on the
asymmetric synthesis of 5,6-dihydroisoquinolines and as an effi-
cient electron withdrawing group to activate the lactam toward the
1,4-addition.
d
¼0.79 (t, J¼7.0 Hz, 3H), 1.08–1.47 (m, 4H), 1.67–1.83 (m,
(75.47 MHz, CDCl3):
d
¼13.8, 23.0, 26.9, 27.8, 33.9, 36.3, 44.2, 47.7,
55.8, 55.9, 62.9, 66.7, 108.4, 111.7, 127.4, 127.5, 128.2, 128.4, 128.6,
129.1, 131.5, 133.1, 133.6, 134.5, 147.4, 147.8, 171.9. LRMS (EI, 70 eV):
m/z (%)¼533 (Mþ, <1), 477 (16), 424 (12), 366 (11), 258 (17), 249
(15), 248 (78), 233 (14), 232 (30), 231 (100), 153 (15), 149 (22), 147
(10), 121 (18), 116 (22), 115 (15), 77 (16), 65 (16). C31H35NO3S2: calcd
23
C 69.76, H 6.61, N 2.62; found: C 69.70, H 6.61, N 2.72. [
a]
þ79.0 (c
D
0.02, CHCl3). The enantiomeric excess determined by CSP HPLC was
>99% by comparison with the racemic mixture. Chiralcel OD, 5%
hexane/2-propanol, 0.4 mL/min; tR[(1S,10bR)-2b]¼35 min (>99%);
tR[(1R,10bS)-2b]¼31.6 min (<1%). The spectroscopic data were
identical to those of racemate.
4. Experimental section
4.1. (1R,10bR)-(D)-1-[1,3-Dithian-2-yl]-8,9-dimethoxy-
10b-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3-one (2a)
4.3. 2-Benzyloxycarbonyl-8,9-dimethoxy-10b-methyl-5,6-
dihydropyrrolo-[2,1-a]isoquinolin-3-one (4a)
To a solution of 1,3-dithiane (0.24 mg, 0.2 mmol) in dry THF
(3 mL), n-BuLi (0.15 mL of a 1.04 M solution in hexanes, 0.15 mmol)
was added at ꢀ78 ꢁC. The resulting mixture was stirred at this
A solution of pyrroloisoquinoline 3a19a (520 mg, 1.99 mmol) in
dry THF (5 mL) was added over a solution of LDA (0.73 M,

5792
C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
4.38 mmol) [obtained from iPr2NH (0.61 mL, 4.38 mmol) and n-BuLi
(3.5 mL of a 1.24 M solution, 4.38 mmol)] at ꢀ78 ꢁC. The reaction
mixture was stirred for 1 h and benzyl chloroformate (0.3 mL,
1.99 mmol) was added. After stirring the mixture for 45 min, a so-
lution of phenylselenyl bromide (672 mg, 0.7 M) in THF (4 mL) was
added, and the reaction was stirred at ꢀ78 ꢁC for 1 h. The reaction
was quenched by addition of HCl (1 M, 10 mL) and allowed to reach
rt. The organic layer was separated, and the aqueous phase was
extracted with Et2O (15 mL) and CH2Cl2 (3ꢂ15 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo to
afford a diastereomeric mixture of selenides. To carry out the oxi-
dative elimination, pyridine (0.65 mL, 7.97 mol) and 30% H2O2
(0.34 mL, 11.9 mmol) were added sequentially to a solution of the
diastereomeric mixture of selenides in dry CH2Cl2 (40 mL) at 0 ꢁC.
The reaction mixture was allowed to reach rt, and stirred for 12 h.
The reaction was quenched by addition of HCl (5% aq, 25 mL), the
organic layer was separated, and extracted with CH2Cl2 (3ꢂ15 mL).
The combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. Flash column chromatography (silicagel, 60% hex-
ane/AcOEt) afforded pyrroloisoquinoline 4a (479 mg, 61%) as
(8), 245 (4), 244 (20), 242 (3), 91 (21), 79 (4), 65 (3). C26H29NO5:
calcd C 71.70, H 6.71, N 3.22; found: C 71.55, H 6.69, N 3.10.
4.5. 2-Butoxycarbonyl-10b-butyl-8,9-dimethoxy-5,6-
dihydropyrrolo[2,1-a]isoquinolin-3-one (4c)
A solution of pyrroloisoquinoline 3b19a (532 mg, 1.75 mmol) in
dry THF (10 mL) was added over a solution of LDA (0.7 M, 3.9 mmol)
[obtained from iPr2NH (0.54 mL, 3.9 mmol) and n-BuLi (3.71 mL of
a 1.05 M solution, 3.9 mmol)] at ꢀ78 ꢁC. The reaction mixture was
stirred for 1 h and butyl chloroformate (0.32 mL, 1.75 mmol) was
added. After stirring the mixture for 45 min, a solution of phenyl-
selenyl bromide (580 mg, 0.7 M) in THF (5 mL) was added, and the
reaction was stirred at ꢀ78 ꢁC for 1 h. The reaction was quenched by
addition of HCl (1 M, 10 mL) and allowed to reach rt. The organic
layer was separated, and the aqueous phase was extracted with Et2O
(15 mL) and CH2Cl2 (3ꢂ15 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo to afford a diastereomeric
mixture of selenides. To carry out the oxidative elimination, pyri-
dine (0.6 mL, 7.02 mol) and 30% H2O2 (0.35 mL, 10.5 mmol) were
added sequentially to a solution of the diastereomeric mixture of
selenides in dry CH2Cl2 (30 mL) at 0 ꢁC. The reaction mixture was
allowed to reach rt, and stirred for 16 h. The reaction was quenched
by addition of HCl (5% aq, 25 mL), the organic layer was separated,
and extracted with CH2Cl2 (3ꢂ15 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated in vacuo. Flash column
chromatography (silicagel, 60% hexane/AcOEt) afforded pyrrolo-
a white solid: mp (Et2O): 128–130 ꢁC. IR (KBr)
NMR (300 MHz, CDCl3):
n
¼1740,1680 cmꢀ1.1H
d
¼1.59 (s, 3H), 262 (dd, J¼16.0, 3.8 Hz, 1H),
2.91 (td, J¼11.9, 6.3 Hz, 1H), 3.18 (ddd, J¼13.1, 11.9, 4.4 Hz, 1H), 3.79
(s, 3H), 3.84 (s, 3H), 4.43 (dd, J¼13.1, 6.3 Hz,1H), 5.23 (s, 2H), 6.60 (s,
1H), 6.70 (s,1H), 7.27–7.40 (m, 5H), 8.10 (s,1H).13C NMR (75.47 MHz,
CDCl3):
d
¼26.1, 28.7, 34.7, 55.6, 55.8, 62.9, 66.4, 108.7, 111.8, 125.3,
127.2, 127.7, 128.0, 128.3, 135.2, 147.5, 148.1, 159.8, 161.2, 164.8. LRMS
(EI, 70 eV): m/z (%)¼394 (Mþþ1, 3), 393 (Mþ, 11), 379 (20), 378 (71),
284 (6), 259 (8), 244 (39), 242 (9),107 (12), 91 (100), 79 (27), 77 (25),
65 (26), 57 (15). C23H23NO5: calcd C 70.21, H 5.89, N 3.56; found: C
69.85, H 5.84, N 3.53.
isoquinoline 4c (477 mg, 68%) as an oil; IR (KBr)
n
¼1740, 1610 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
¼0.68–0.86 (m, 6H), 0.97–1.28 (m, 4H),
1.31–1.40 (m, 2H), 1.54–1.66 (m, 2H), 1.85–2.00 (m, 2H), 2.58 (dd,
J¼15.8, 3.5 Hz, 1H), 2.85 (ddd, J¼15.8, 11.5, 6.3 Hz, 1H), 3.08 (ddd,
J¼12.7, 11.9, 4.4 Hz, 1H), 3.74 (s, 3H), 3.81 (s, 3H), 4.15 (t, J¼6.7 Hz,
2H), 4.37 (dd, J¼12.7, 5.5 Hz, 1H), 6.53 (s, 1H), 6.68 (s, 1H), 7.94 (s,
4.4. 2-Benzyloxycarbonyl-10b-butyl-8,9-dimethoxy-5,6-
dihydropyrrolo[2,1-a]isoquinolin-3-one (4b)
1H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.8,13.4,18.8, 22.3, 25.0, 28.5,
30.2, 34.6, 38.4, 55.5, 55.8, 64.6, 65.8, 108.8, 111.8, 125.1, 127.7, 129.0,
147.3, 148.0, 158.9, 161.4, 165.5. LRMS (EI, 70 eV): m/z (%)¼401
(Mþ,1), 345 (23), 344 (100), 288 (33), 258 (7), 244 (14), 242 (10), 200
(9),115 (5), 91 (8), 57 (16), 56 (10), 55 (14). C23H31NO5: calcd C 68.80,
H 7.78, N 3.49; found C 68.64, H 7.69, N 3.54.
A solution of pyrroloisoquinoline 3b19a (465 mg, 1.53 mmol) in
dry THF (8 mL) was added over a solution of LDA (0.7 M, 3.4 mmol)
i
[obtained from Pr2NH (0.47 mL, 3.4 mmol) and n-BuLi (2.7 mL of
a 1.24 M solution, 3.4 mmol)] at ꢀ78 ꢁC. The reaction mixture was
stirred for 1 h and benzyl chloroformate (0.28 mL, 1.53 mmol) was
added. After stirring the mixture for 45 min, a solution of phenyl-
selenyl bromide (507 mg, 0.7 M) in THF (3 mL) was added, and the
reaction was stirred at ꢀ78 ꢁC for 1 h. The reaction was quenched
by addition of HCl (1 M, 10 mL) and allowed to reach rt. The organic
layer was separated, and the aqueous phase was extracted with
Et2O (15 mL) and CH2Cl2 (3ꢂ15 mL). The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo to afford a di-
astereomeric mixture of selenides. To carry out the oxidative
elimination, pyridine (0.5 mL, 6.14 mol) and 30% H2O2 (0.3 mL,
9.21 mmol) were added sequentially to a solution of the di-
astereomeric mixture of selenides in dry CH2Cl2 (30 mL) at 0 ꢁC. The
reaction mixture was allowed to reach rt, and stirred for 16 h. The
reaction was quenched by addition of HCl (5% aq, 25 mL), the or-
ganic layer was separated, and extracted with CH2Cl2 (3ꢂ15 mL).
The combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. Flash column chromatography (silicagel, 70% hex-
ane/AcOEt) afforded pyrroloisoquinoline 4b (501 mg, 75%) as an oil:
4.6. 2-N-Benzylcarbamoyl-8,9-dimethoxy-10b-methyl-5,6,-
dihydropyrrolo[2,1-a]isoquinolin-3-one (4d)
Benzylamine (0.08 mL, 0.7 mmol) and water (0.04 mL, 1.9 mmol)
were added drop wise over lactam 4a (154 mg, 0.4 mmol) at rt and
the reaction mixture was stirred for 18 h. Flash column chromato-
graphy (silicagel, 70% hexane/AcOEt) afforded pyrroloisoquinoline
4d (90 mg, 60%) as a white solid: mp (Et2O) 167–168 ꢁC. IR (KBr)
n
¼3280, 3060,1695 cmꢀ1. 1H NMR (300 MHz, CDCl3):
¼1.62 (s, 3H),
d
2.69 (dd, J¼16.2, 3.9 Hz, 1H), 2.93 (ddd, J¼16.2, 11.9, 6.7 Hz, 1H), 3.27
(td, J¼13.2, 4.7 Hz, 1H), 3.81 (s, 3H), 3.87 (s, 3H), 4.38 (dd, J¼13.2,
6.1 Hz,1H), 4.48–4.64 (m, 2H), 6.58 (s,1H), 6.73 (s,1H), 7.21–7.29 (m,
5H), 8.18 (s, 1H), 8.93 (t, J¼11.5, 5.7 Hz, 1H). 13C NMR (75.47 MHz,
CDCl3):
d¼26.2, 28.9, 34.9, 42.8, 55.8, 56.0, 63.4, 108.8, 111.8, 124.7,
127.2, 127.5, 127.7, 127.9, 128.5, 137.8, 147.7, 148.3, 157.0, 160.6, 167.5.
LRMS (EI, 70 eV): m/z (%)¼393 (Mþþ1, 14), 392 (Mþ, 44), 378 (15),
377 (Mþꢀ15, 58), 286 (29), 272 (22), 259 (7), 245 (20), 244 (25), 228
(6), 207 (6), 206 (29), 200 (10), 115 (6), 107 (9), 106 (100), 91 (27), 79
(11), 77 (9), 65 (9). C23H24N2O4: calcd C 70.39, H 6.16, N 7.14; found: C
70.11, H 6.02, N 7.28.
IR (KBr)
n
¼1795, 1640 cmꢀ1. 1H NMR (300 MHz, CDCl3):
¼0.83 (t,
d
J¼7.1 Hz, 3H), 1.05–1.14 (m, 4H), 1.98 (t, J¼6.7 Hz, 2H), 2.64 (dd,
J¼15.8, 3.5 Hz, 1H), 2.93 (ddd, J¼15.8, 11.8, 6.3 Hz, 1H), 3.15 (ddd,
J¼13.1, 11.8, 4.3 Hz, 1H), 3.82 (s, 3H), 3.88 (s, 3H), 4.46 (dd, J¼13.1,
6.3 Hz, 1H), 5.21 (s, 2H), 6.59 (s, 1H), 6.68 (s, 1H), 7.26–7.45 (m, 5H),
4.7. Conjugate addition reactions of organocuprates to
pyrrolo[2,1-a]isoquinolones 4a,b. General procedure
7.99 (s, 1H); 13C NMR (75.47 MHz, CDCl3):
d¼13.7, 22.5, 25.2, 28.7,
34.8, 38.7, 55.7, 56.0, 66.1, 66.5, 108.9, 111.9, 125.3, 127.7, 128.1, 128.4,
128.9, 135.3, 147.5, 148.2, 159.4, 161.3, 165.6. LRMS (EI, 70 eV): m/z
(%)¼435 (Mþ, 2), 380 (4), 379 (25), 378 (100), 328 (2), 327 (4), 284
Methyllithium or n-butyllithium (10 mmol) was added drop
wise over a suspension of CuI (5 mmol) in dry THF (10 mL) at 0 ꢁC.

C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
5793
After 30 min, the mixture was cooled to ꢀ78 ꢁC, and a solution of
4.7.3. (1SR,2SR,10bSR)-2-Benzyloxycarbonyl-1-butyl-8,9-
dimethoxy-10b-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-
a]isoquinolin-3-one (5c) and (1SR,2SR,10bSR)-1-butyl-2-
butoxycarbonyl-8,9-dimethoxy-10b-methyl-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinolin-3-one (5c0)
According to the general procedure, a solution of 4a (95 mg,
0.24 mmol) in dry THF (10 mL) was treated with the organocuprate,
prepared from CuI (231 mg, 1.2 mmol) and n-BuLi (1.5 mL of a 1.6 M
solution in hexanes, 2.4 mmol). Flash column chromatography
(silica gel, 50% hexane/AcOEt) afforded 5c and 5c0. Major product 5c
lactams 4a,b (1 mmol) in THF (10 mL) was added. The reaction
mixture was stirred for 3 h, allowed to warm up to 0 ꢁC, and stirred
at this temperature for 12 h. The reaction was quenched by se-
quential addition of NH4OH (12% aq) (20 mL) and NH4Cl (satd)
(10 mL) at 0 ꢁC. After allowing the mixture to warm up to rt, the
organic layer was separated, and the aqueous phase was extracted
with CH2Cl2 (3ꢂ15 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. Flash column chromatography
(silicagel, 70% hexane/AcOEt) afforded pyrroloisoquinolones 5 and/
or 6.
(56 mg, 51%) as an oil: IR (KBr)
(300 MHz, CDCl3):
n
¼1740, 1690 cmꢀ1
.
1H NMR
d
¼0.79 (t, J¼7.1 Hz, 3H), 1.05–1.27 (m, 4H), 1.41
4.7.1. (1SR,2SR,10bSR)-2-Benzyloxycarbonyl-8,9-dimethoxy-
1,10b-dimethyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3-one (5a)
(s, 3H), 1.66–2.04 (m, 2H), 2.61–2.70 (m, 1H), 2.77 (dd, J¼11.5,
2.8 Hz, 1H), 2.86–3.08 (m, 2H), 3.37 (d, J¼11.1 Hz, 1H), 3.84 (s, 3H),
3.85 (s, 3H), 4.28–4.35 (m, 1H), 5.21 (d, J¼5.5 Hz, 2H), 6.58 (s, 1H),
6.74 (s, 1H), 7.31–7.37 (m, 5H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.8,
According to the general procedure, a solution of 4a (157 mg,
0.4 mmol) in dry THF (10 mL) was treated with the organocuprate,
prepared from CuI (228 mg, 2.0 mmol) and MeLi (2.5 mL of a 1.6 M
solution in hexanes, 4.0 mmol). Flash column chromatography
(silica gel, 70% hexane/AcOEt) afforded 5a (140 mg, 85%) as a single
23.1, 22.7, 28.9, 29.8, 30.5, 35.1, 49.2, 55.6, 55.8, 56.0, 62.0, 67.2,
107.7, 111.8, 125.2, 128.2, 128.4, 128.5, 133.8, 135.4, 147.7, 147.9, 166.9,
170.4. LRMS (EI, 70 eV): m/z (%)¼452 (Mþþ1, 8), 451 (Mþ, 23), 437
(30), 436 (100), 328 (10), 301 (21), 258 (11), 206 (11), 205 (12), 91
(33). C27H33NO5: calcd C 71.82, H 7.37, N 3.10; found C 71.60; H 7.54;
diastereomer, white solid: mp (Et2O) 104–105 ꢁC. IR (KBr)
n
¼1736,
N 3.28. Minor product 5c0 (24 mg, 24%) as an oil: IR (KBr)
n
¼1745,
1692 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
¼1.36 (t, J¼6.7 Hz, 3H), 1.41
1669 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
¼0.86–0.95 (m, 6H), 1.23–
(s, 3H), 2.61–3.04 (m, 4H), 3.36 (d, J¼11.9 Hz, 1H), 3.84 (s, 6H), 4.29–
1.42 (m, 11H), 1.61–2.04 (m, 2H), 2.60–2.70 (m, 1H), 2.77 (dd, J¼11.1,
3.0 Hz, 1H), 2.86–3.06 (m, 2H), 3.31 (d, J¼11.1 Hz, 1H), 3.86 (s, 6H),
4.17 (t, J¼6.7 Hz, 2H), 4.27–4.34 (m, 1H), 6.59 (s, 1H), 6.77 (s, 1H). 13C
4.32 (m,1H), 5.21 (s, 2H), 6.57 (s,1H), 6.69 (s,1H), 7.25–7.35 (m, 5H).
13C NMR (75.47 MHz, CDCl3):
d
¼13.9, 21.9, 28.8, 34.8, 44.2, 55.6,
55.7, 55.9, 61.5, 66.9, 107.6, 11.7, 124.9, 127.8, 128.0, 128.4, 133.2,
135.4, 147.6, 147.7, 166.3, 169.2. LRMS (EI, 70 eV): m/z (%)¼409 (Mþ,
8), 395 (26), 394 (100), 259 (32), 258 (14), 244 (20), 206 (10), 204
(10), 91(52). C24H27NO5: calcd C 70.40, H 6.65, N 3.42; found C
70.35, H 6.43, N 3.16.
NMR (75.47 MHz, CDCl3):
d
¼13.6, 13.9, 19.0, 22.8, 23.1, 29.0, 29.9,
30.4, 30.5, 35.1, 49.1, 55.7, 55.8, 56.1, 62.0, 65.4, 107.8, 111.8, 125.3,
133.9, 147.7, 147.9, 167.1, 170.7. LRMS (EI, 70 eV): m/z (%)¼418
(Mþþ1, 5), 417 (Mþ, 15), 403 (25), 402 (Mþꢀ15, 100), 328 (26), 300
(7), 206 (9), 205 (11), 55 (3). C24H32NO5: calcd C 69.04, H 8.45, N
3.35; found C 68.79; H 8.56; N 3.47.
4.7.2. (1SR,2SR,10bSR)-2-Benzyloxycarbonyl-10b-butyl-8,9-
dimethoxy-1-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3-one (5b) and (1RS,2RS,10bSR)-2-benzyloxycarbonyl-10b-butyl-
8,9-dimethoxy-1-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3-one (6b)
According to the general procedure, a solution of 4b (159 mg,
0.36 mmol) in dry THF (10 mL) was treated with the organocuprate,
prepared from CuI (348 mg, 1.8 mmol) and MeLi (2.8 mL of a 1.3 M
solution in hexanes, 3.6 mmol). Flash column chromatography
(silica gel, 70% hexane/AcOEt) afforded a diastereomeric mixture of
5b and 6b in a 67:33 diastereomeric ratio (97 mg, 59%). Both di-
astereomers were separated by chromatography and characterized
separately. Major diastereomer 5b, oil (68 mg, 41%): IR (KBr)
4.7.4. (1SR,2SR,10bSR)-2-Benzyloxycarbonyl-1,10b-dibutyl-8,9-
dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one
(5d), (1RS,2RS,10bSR)-2-benzyloxycarbonyl-1,10b-dibutyl-8,9-
dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one
(6d), and (1SR,2SR,10bSR)-1,10b-dibutyl-2-butoxycarbonyl-8,9-
dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3-one (5f)
According to the general procedure, a solution of 4b (167 mg,
0.27 mmol) in dry THF (10 mL) was treated with the organocuprate,
prepared from CuI (255 mg, 1.3 mmol) and n-BuLi (2.2 mL of
a 1.24 M solution in hexanes, 2.73 mmol). Flash column chroma-
tography (silica gel, 50% hexane/AcOEt) afforded as major product
a diastereomeric mixture of 5d and 6d in a 70:30 diastereomeric
ratio (76 mg, 57%), together with 5f (18.5 mg, 15%) as minor prod-
uct. Both diastereomers were separated by chromatography and
characterized separately. Major diastereomer 5d, oil (59 mg, 44%):
n
¼1745, 1700 cmꢀ1. 1H NMR (300 MHz, CDCl3):
¼0.85 (t, J¼6.5 Hz,
d
3H), 1.08–1.25 (m, 4H), 1.36 (d, J¼7.1 Hz, 3H), 1.82–1.85 (m, 2H),
2.64–2.70 (m, 1H), 2.74 (dd, J¼12.3, 7.1 Hz, 1H), 2.81–3.05 (m, 2H),
3.47 (d, J¼12.3 Hz, 1H), 3.85 (s, 6H), 4.37–4.42 (m, 1H), 5.21 (s, 2H),
6.58 (s, 1H), 6.70 (s, 1H), 7.29–7.37 (m, 5H). 13C NMR (75.47 MHz,
IR (KBr)
n
¼1745, 1700 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
¼0.76–
CDCl3):
d
¼13.7,13.9, 23.2, 27.0, 29.0, 36.5, 36.8, 45.0, 55.8, 56.0, 56.2,
0.94 (m, 6H), 1.01–1.40 (m, 8H), 1.60–1.98 (m, 4H), 2.61–2.66 (m,
1H), 2.73–2.78 (m, 1H), 2.83–3.04 (m, 2H), 3.45 (d, J¼11.1 Hz, 1H),
3.84 (s, 3H), 3.86 (s, 3H), 4.35–4.39 (m, 1H), 5.21 (d, J¼5.5 Hz, 2H),
6.58 (s, 1H), 6.73 (s, 1H), 7.30–7.36 (m, 5H). 13C NMR (75.47 MHz,
64.3, 67.1, 107.4, 111.9, 125.3, 132.7, 135.6, 128.0, 128.1, 128.5, 147.8,
167.7, 169.6; LRMS (EI, 70 eV): m/z (%)¼451 (Mþ, 2), 395 (26), 394
(100), 286 (13), 259 (39), 258 (16), 244 (23), 91 (75), 57 (7).
C27H33NO5: calcd C 71.83, H 7.37, N 3.10; found C 71.62, H 7.15, N
CDCl3):
d
¼13.8, 13.9, 22.8, 23.1, 27.2, 29.0, 30.0, 30.1, 36.4, 37.5, 49.8,
3.05. Minor diastereomer 6b, oil (29 mg, 18%): IR (KBr)
n
¼1745,
55.8, 56.0, 56.1, 64.8, 67.3, 107.4, 111.9, 125.3, 133.4, 135.4, 128.3,
128.5, 128.6, 147.8, 168.1, 170.7; LRMS (EI, 70 eV): m/z (%)¼493 (Mþ,
1), 437 (27), 436 (Mþꢀ57, 100), 328 (10), 301 (16), 258 (10), 244 (7),
91 (23), 55 (5). C30H39NO5: calcd C 72.99, H 7.96, N 2.84; found C
72.62, H 8.11, N 3.03. Minor diastereomer 6d, oil (18 mg, 13%): IR
1700 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d
¼0.66 (d, J¼7.1 Hz, 3H),
0.70 (t, J¼6.5 Hz, 3H), 0.90–1.23 (m, 4H),1.71–2.0 (m, 2H), 2.57–2.74
(m, 2H), 2.79–2.88 (m, 1H), 3.00–3.12 (m, 1H), 3.09 (d, J¼1.6 Hz,1H),
3.80 (s, 6H), 4.38–4.45 (m, 1H), 5.23 (d, J¼1.6 Hz, 2H), 6.49 (s, 1H),
6.55 (s, 1H), 7.29–7.43 (m, 5H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.7,
(KBr)
n
¼1745, 1700 cmꢀ1. 1H NMR (300 MHz, CDCl3):
¼0.69–1.28
d
19.1, 23.0, 27.4, 28.9, 37.4, 43.6, 42.9, 55.7, 56.1, 57.4, 67.2, 67.5, 109.0,
111.4, 125.3, 127.9, 135.4, 128.3, 128.4, 128.5, 147.6, 147.7, 167.9, 169.9.
LRMS (EI, 70 eV): m/z (%)¼451 (Mþ, 2), 395 (26), 394 (100), 286 (9),
259 (23), 258 (9), 244 (14), 91 (28). C27H33NO5: calcd C 71.83, H 7.37,
N 3.10; found: C 71.48, H 7.09, N 2.99.
(m, 16H), 1.73–1.86 (m, 2H), 2.58–2.80 (m, 3H), 3.08 (td, J¼12.3,
4.4 Hz, 1H), 3.27 (d, J¼1.2 Hz, 1H), 3.84 (s, 3H), 3.87 (s, 3H), 4.43 (dd,
J¼12.7, 5.5 Hz, 1H), 5.26 (d, J¼2.4 Hz, 2H), 6.49 (s, 1H), 6.57 (s, 1H),
7.19–7.43 (m, 5H). 13C NMR (75.47 MHz, CDCl3):
d¼13.8, 14.2, 22.1,
23.0, 27.4, 28.3, 28.9, 29.1, 29.7, 36.8, 46.6, 55.7, 56.1, 56.1, 67.2, 67.6,

5794
C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
103.0, 111.4, 127.4, 128.2, 128.3, 128.5, 132.7, 135.6, 147.6, 147.8, 168.1,
170.4. LRMS (EI, 70 eV): m/z (%)¼493 (Mþ, <1), 437 (29), 436
(Mþꢀ57, 100), 347 (19), 345 (15), 344 (46), 343 (23), 329 (35), 328
(14), 301 (22), 258 (15), 244 (18), 91 (51), 57 (16), 55 (16).
C30H39NO5: calcd C 72.99, H 7.96, N 2.84; found C 72.60, H 8.13, N
NMR (300 MHz, CDCl3):
d
¼0.66–0.87 (m, 6H), 0.94 (t, J¼7.3 Hz,
3H), 1.00–1.50 (m, 10H), 1.60–2.04 (m, 6H), 2.58–2.66 (m, 2H),
2.75 (dd, J¼15.5, 5.5 Hz, 1H), 3.08 (td, J¼12.3, 4.4 Hz, 1H), 3.21 (s,
1H), 3.85 (s, 3H), 3.87 (s, 3H), 4.21 (t, J¼6.7 Hz, 2H), 4.43 (dd,
J¼12.3, 5.5 Hz, 1H), 6.52 (s, 1H), 6.57 (s, 1H). 13C NMR (75.47 MHz,
3.06. Minor product 5f, oil (18.5 mg, 15%): IR (KBr)
n
¼1737,
CDCl3):
d
¼13.7, 13.8, 13.9, 19.1, 22.1, 23.2, 27.5, 28.3, 29.1, 30.4,
1692 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d¼0.83–0.94 (m, 9H), 1.08–
30.5, 37.6, 44.3, 48.5, 54.4, 55.7, 56.1, 65.6, 67.6, 109.1, 111.3, 127.4,
128.1, 147.6, 147.7, 168.3, 170.7. LRMS (EI, 70 eV): m/z (%)¼459 (Mþ,
<1), 431 (1), 375 (22), 374 (100), 328 (27), 302 (31), 300 (7), 258
(5), 244 (2), 57 (10), 55 (1). C27H41NO5: calcd C 70.56, H 8.99, N
3.05; found C 70.38, H 9.11, N 3.12.
1.46 (m, 10H), 1.57–2.14 (m, 6H), 2.59–3.05 (m, 4H), 3.4 (d,
J¼11.5 Hz, 1H), 3.86 (s, 6H), 4.20 (t, J¼6.7 Hz, 2H), 4.36 (dd, J¼11.9,
3.6 Hz, 1H), 6.58 (s, 1H), 6.74 (s, 1H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.6, 13.8, 13.9, 19.0, 22.8, 23.1, 27.1, 28.9, 29.9, 30.1, 30.4, 36.3,
37.4, 49.6, 55.6, 55.7, 56.0, 64.7, 65.3, 107.3, 111.8, 125.2, 133.4, 147.7,
168.2, 170.9. LRMS (EI, 70 eV): m/z (%)¼459 (Mþ, <1), 403 (26), 402
(100), 328 (22), 300 (9), 258 (10), 244 (6), 57 (10), 55 (6).
C27H41NO5: calcd C 70.56, H 8.99, N 3.05; found C 70.39, H 9.04, N
3.12.
4.8. (1SR,10bSR)-8,9-Dimethoxy-1,10b-dimethyl-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinolin-3-one (7)
A solution of (1SR,2SR,10bSR)-5a (163 mg, 0.4 mmol) in MeOH
(30 mL) was treated with hydrogenated (H2, 20 psi) in the presence
of Pd/C (0.2 mmol) at rt for 2 days. The crude reaction mixture was
filtered through Celite and the solvent evaporated. The residue was
dissolved in toluene (5 mL) and the solution heated under reflux for
12 h. Flash column chromatography (silica gel, AcOEt) afforded the
4.7.5. (1SR,2SR,10bSR)-10b-Butyl-2-butoxycarbonyl-8,9-dimethoxy-
1-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (5e)
and (1RS,2RS,10bSR)-10b-butyl-2-butoxycarbonyl-8,9-dimethoxy-1-
methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (6e)
According to the general procedure, a solution of 4c (106 mg,
0.26 mmol) in dry THF (4 mL) was treated with the organo-
cuprate, prepared from CuI (252 mg, 1.32 mmol) and MeLi
(1.65 mL of a 1.6 M solution in hexanes, 2.64 mmol). Flash column
chromatography (silica gel, 70% hexane/AcOEt) afforded a di-
astereomeric mixture of 5e and 6e in a 61:39 diastereomeric ratio
(80 mg, 75%). Both diastereomers were separated by chromato-
graphy and characterized separately. Major diastereomer 5e, oil
pyrroloisoquinolone 7 (10 mg, 44%): IR (KBr)
(300 MHz, CDCl3):
n
¼1684 cmꢀ1. 1H NMR
d
¼1.37 (d, J¼5.9 Hz, 3H), 1.40 (s, 3H), 2.20–2.40
(m, 2H), 2.49 (dd, J¼13.5, 6.3 Hz, 1H), 2.59–2.66 (m, 1H), 2.80–3.02
(m, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.28–4.35 (m, 1H), 6.58 (s, 1H),
6.75 (s, 1H). 13C NMR (75.47 MHz, CDCl3):
d¼15.1, 21.5, 29.0, 34.4,
39.2, 40.3, 55.8, 56.0, 62.9, 107.8, 111.8, 125.1, 134.6, 147.7, 171.4.
LRMS (EI, 70 eV): m/z (%)¼276 (Mþþ1, 4), 275 (Mþ, 17), 261 (17),
260 (Mþꢀ15, 100), 245 (3), 244 (6), 216 (3), 205 (4), 204 (4), 190 (3),
130 (3), 57 (2). C16H21NO3: calcd C 69.79, H 7.69, N 5.09; found: C
69.89, H 7.86, N 4.77.
(49 mg, 47%): IR (KBr)
CDCl3):
n
¼1734, 1684 cmꢀ1
.
1H NMR (300 MHz,
d
¼0.82–0.94 (m, 6H), 1.08–1.34 (m, 6H), 1.37 (d, J¼6.7 Hz,
3H), 1.58–1.69 (m, 2H), 1.79–1.88 (m, 2H), 2.60–2.95 (m, 3H), 3.03
(dd, J¼12.3, 3.4 Hz, 1H), 3.39 (d, J¼12.3 Hz, 1H), 3.85 (s, 3H), 3.86
(s, 3H), 4.11–4.25 (m, 2H), 4.36–4.43 (m, 1H), 6.58 (s, 1H), 6.71 (s,
4.9. (1RS,10bSR)-10b-Butyl-8,9-dimethoxy-1-methyl-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (8)
1H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.7, 13.9, 18.9, 23.2, 27.0,
29.0, 30.5, 36.5, 36.8, 44.9, 55.7, 56.0, 56.2, 64.3, 65.3, 107.4, 111.8,
125.3, 132.8, 147.7, 167.9, 169.7. LRMS (EI, 70 eV): m/z (%)¼417 (Mþ,
2), 361 (24), 360 (100), 286 (37), 260 (8), 259 (10), 258 (19), 244
(11), 200 (3), 91 (3), 57 (8). C24H35NO5: calcd C 69.04, H 8.45, N
3.35; found C 68.99, H 8.37, N 3.41. Minor diastereomer 6e, oil
NaOH (70 mg, 1.7 mmol) was added to a solution of
(1RS,2RS,10bSR)-6e (26 mg, 0.07 mmol) in THF:H2O:MeOH (3:2:1)
(2 mL) at rt, and the resulting mixture was stirred for 12 h. H2O
(5 mL) was added and the reaction mixture was extracted with
AcOEt (10 mL). The aqueous phase was treated with 1 M HCl till
pH¼1 and was extracted with AcOEt (3ꢂ10 mL). The combined
organic extracts were dried (Na2SO4), and concentrated in vacuo.
The residue was dissolved in toluene (3 mL) and the solution
heated under reflux for 12 h. Flash column chromatography (silica
gel, AcOEt) afforded 8 (17 mg, 86%) as a white solid: mp (AcOEt)
(31 mg, 31%): IR (KBr)
CDCl3):
n
.
¼1735, 1691 cmꢀ1 1H NMR (300 MHz,
d
¼0.68 (d, J¼7.1 Hz, 3H), 0.78 (t, J¼6.7 Hz, 3H), 0.93 (t,
J¼7.3 Hz, 3H), 1.04–1.47 (m, 5H), 1.55–2.01 (m, 5H), 2.58–2.89 (m,
3H), 3.04 (d, J¼1.6 Hz, 1H), 3.10 (dd, J¼12.3, 4.4 Hz, 1H), 3.89 (s,
6H), 4.20 (td, J¼6.7, 2.3 Hz, 2H), 4.4 (dd, J¼13.1, 4.4 Hz, 1H), 6.53 (s,
1H), 6.58 (s, 1H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.7, 13.8, 19.1,
120–122 ꢁC; IR (KBr)
n
¼1686 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
23.2, 27.5, 28.9, 30.5, 37.4, 43.6, 43.0, 55.7, 56.1, 57.5, 65.6, 67.4,
108.9, 111.3, 127.3, 127.9, 147.6, 147.7, 168.1, 170.2. LRMS (EI, 70 eV):
m/z (%)¼417 (Mþ, 2), 361 (24), 360 (100), 286 (32), 258 (16), 244
(11), 230 (4), 214 (3), 200 (3), 57 (6). C24H35NO5: calcd C 69.04, H
8.45, N 3.35; found C 68.85, H 8.28, N 3.48.
d
¼0.56 (d, J¼6.7 Hz, 3H), 0.81 (t, J¼7.1 Hz, 3H), 1.10–1.37 (m, 4H),
1.74–2.04 (m, 3H), 2.30–3.07 (m, 5H), 3.86 (s, 6H), 4.40 (dd, J¼12.3,
4.8 Hz, 1H), 6.5 (s, 1H), 6.60 (s, 1H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.9, 18.4, 23.3, 28.9, 36.2, 38.9, 40.0, 42.5, 38.9, 55.7, 56.1, 67.7,
108.8, 111.3, 127.0, 129.0, 147.4, 147.7, 172.9. LRMS (EI, 70 eV): m/z
(%)¼317 (Mþ, 1), 262 (2), 261 (16), 260 (100), 244 (4), 216 (2), 130
(4), 83 (2). C19H27NO3: calcd C 71.89, H 8.57, N 4.41; found: C 71.84,
H 8.53, N 4.28.
4.7.6. (1SR,2SR,10bSR)-1,10b-Dibutyl-2-butoxycarbonyl-8,9-
dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one
(5f) and (1RS,2RS,10bSR)-1,10b-dibutyl-2-butoxycarbonyl-8,9-
dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (6f)
According to the general procedure, a solution of 4c (98 mg,
0.24 mmol) in dry THF (5 mL) was treated with the organo-
cuprate, prepared from CuI (233 mg, 1.32 mmol) and n-BuLi
(1.5 mL of a 1.6 M solution in hexanes, 2.44 mmol). Flash column
chromatography (silica gel, 70% hexane/AcOEt) afforded a di-
astereomeric mixture of 5f and 6f in a 66:34 diastereomeric ratio
(87 mg, 78%). Both diastereomers were separated by chromato-
graphy and characterized separately. Major diastereomer 5f, oil
(55 mg, 52%) (spectroscopic data are described above). Minor
4.10. Tandem conjugate addition of organocuprates/a-
alkylation reactions on pyrrolo[2,1-a]isoquinolone 3a.
General procedure
Methyllithium (6 mmol) was added drop wise over a suspension
of CuI (3 mmol) in dry THF (10 mL) at 0 ꢁC. After 30 min, the mix-
ture was cooled to ꢀ78 ꢁC, and a solution of lactam 4a (1 mmol) in
THF (10 mL) was added. The reaction mixture was stirred for 3 h,
allowed to warm up to 0 ꢁC, and stirred at this temperature for 12 h.
After allowing the mixture to warm up to rt, methyl or allyl iodide
(1.2 mmol) was added and the reaction mixture was stirred for
diastereomer 6f, oil (30 mg, 26%). IR (KBr)
n
¼1730, 1695 cmꢀ1. 1H

C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
5795
24 h. The reaction was quenched by sequential addition of NH4OH
(12% aq) (10 mL), the organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3ꢂ15 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. Flash
column chromatography (silicagel, 70% hexane/AcOEt) afforded
pyrroloisoquinolones 9.
(%)¼450 (Mþþ1, 7), 449 (Mþ, 23), 436 (27), 434 (Mþꢀ15, 100),
300(13), 298 (11), 284 (13), 258 (27), 91 (72), 83 (11), 71 (15), 57
(19), 55 (11). C27H31NO5: calcd C 72.14, H 6.95, N 3.12; found C
72.21, H 7.29, N 2.97. Minor diastereomer 9b0, oil (16 mg, 10%): IR
(KBr)
n
¼1736, 1687 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
¼0.98 (d,
J¼7.1 Hz, 3H), 1.53 (s, 3H), 2.28–2.36 (m, 1H), 2.47–2.60 (m, 2H),
2.80–2.93 (m, 2H), 3.05 (td, J¼12.7, 3.6 Hz, 1H), 3.79 (s, 3H), 3.83 (s,
3H), 4.26–4.33 (m, 1H), 4.68 (d, J¼11.9 Hz, 1H), 4.78 (d, J¼11.9 Hz,
1H), 5.14–5.21 (m, 2H), 5.70–5.86 (m, 1H), 6.32 (s, 1H), 6.47 (s, 1H),
4.10.1. (1SR,2RS,10bSR)-2-Benzyloxycarbonyl-8,9-dimethoxy-1,2,10b-
trimethyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (9a)
and (1SR,2SR,10bSR)-2-benzyloxycarbonyl-8,9-dimethoxy-1,2,10b-
trimethyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (9a0)
According to the general procedure, a solution of 4a (144 mg,
0.4 mmol) in dry THF (10 mL) was treated with the organocuprate,
prepared from CuI (209 mg, 1.1 mmol) and MeLi (1.4 mL of a 1.6 M
solution in hexanes, 2.2 mmol) and quenched by addition of MeI
(0.03 mL, 04 mmol). Flash column chromatography (silica gel, 70%
hexane/AcOEt) afforded a diastereomeric mixture of 9a and 9a0 in
an 86:14 diastereomeric ratio (88 mg, 57%). Both diastereomers
were separated by chromatography and characterized separately.
6.87–7.25 (m, 5H). 13C NMR (75.47 MHz, CDCl3):
d
¼12.9, 28.1, 32.5,
36.7, 36.8, 45.2, 55.7, 55.9, 59.3, 63.4, 66.7, 110.4, 111.9, 119.8, 127.5,
128.1, 128.2, 128.6, 130.3, 133.5, 134.9, 146.4, 147.2, 170.6, 172.0.
LRMS (EI, 70 eV): m/z (%)¼450 (Mþþ1, 11), 449 (Mþ, 36), 435 (30),
434 (Mþꢀ15, 100), 284 (13), 258 (25), 91 (37), 79 (4), 71 (6), 57 (7),
55 (4). C27H31NO5: calcd C 72.14, H 6.95, N 3.12; found C 72.33, H
7.7.31, N 2.94.
4.11. Conjugate addition reactions of enolate anions to
pyrrolo[2,1-a]isoquinolones 4a,b. General procedure
Major diastereomer 9a, oil (76 mg, 49%): IR (KBr)
n
¼1733,
1686 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
¼1.25 (d, J¼7.5 Hz, 3H),1.40
Methyl cyanoacetate or dimethyl malonate (2 mmol) was added
drop wise over a solution of NaNH2 (1 mmol) and DMPU (22 or
12 mmol) in dry THF (30 mL) at rt. After 5 min, a solution of lactams
4a,b (1 mmol) in dry THF (10 mL) was added. The reaction mixture
was heated under reflux for 3–8 h. Then the reaction was quenched
by addition of H2O (10 mL) at rt. The organic layer was separated,
and the aqueous phase was extracted with AcOEt (3ꢂ15 mL).
The combined organic extracts were washed H2O (2ꢂ10 mL) and
NaCl (sat) (2ꢂ10 mL), dried (Na2SO4) and concentrated in vacuo.
Flash column chromatography afforded pyrroloisoquinolones
10 and/or 11.
(s, 3H), 1.42 (s, 3H), 2.24 (q, J¼7.5 Hz, 1H), 2.64 (dd, J¼15.7, 3.0 Hz,
1H), 2.89 (ddd, J¼15.7, 12.3, 6.3 Hz, 1H), 3.12 (td, J¼12.3, 4.4 Hz, 1H),
3.83 (s, 3H), 3.84 (s, 3H), 4.40 (dd, J¼12.9, 5.0 Hz, 1H), 5.12 (d,
J¼12.3 Hz, 1H), 5.28 (d, J¼12.3 Hz, 1H), 6.55 (s, 1H), 6.64 (s, 1H),
7.27–7.39 (m, 5H). 13C NMR (75.47 MHz, CDCl3):
d¼11.8, 21.7, 22.6,
28.7, 35.0, 50.7, 55.8, 56.0, 56.4, 61.8, 67.0, 107.4, 111.7, 124.4, 128.4,
128.5, 128.6, 135.3, 135.8, 147.7, 147.8, 170.7, 171.5. LRMS (EI, 70 eV):
m/z (%)¼424 (Mþþ1, 6), 423 (Mþ, 22), 409 (27), 408 (Mþꢀ15, 100),
274 (6), 273 (6), 258 (22), 91 (24), 83 (6), 55 (6). C25H29NO5: calcd C
70.90, H 6.90, N 3.31; found C 70.68, H 7.03, N 3.24. Minor di-
astereomer 9a0, oil (12 mg, 8%): IR (KBr)
NMR (300 MHz, CDCl3):
n
¼1743, 1686 cmꢀ1
.
1H
d
¼0.99 (d, J¼7.5 Hz, 3H), 1.53 (s, 3H), 1.58
4.11.1. (1RS,2SR,10bSR)-2-Benzyloxycarbonyl-1-(cyano-
methoxycarbonylmethyl)-8,9-dimethoxy-10b-methyl-
(s, 3H), 2.33–2.48 (m, 1H), 2.56–2.70 (m, 1H), 2.82–2.94 (m, 1H),
3.08 (td, J¼12.7, 3.2 Hz, 1H), 3.80 (s, 3H), 3.83 (s, 3H), 4.27–4.35 (m,
1H), 4.68 (d, J¼12.3 Hz,1H), 4.83 (d, J¼12.3 Hz,1H), 6.36 (s,1H), 6.47
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (10a)
According to the general procedure, 4a (195 mg, 0.5 mmol) was
treated with a solution of NaNH2 (20 mg, 0.5 mmol), DMPU (1.3 mL,
10.9 mmol) and methyl cyanoacetate (0.1 mL, 1.0 mmol) in dry THF
(15 mL) for 3 h under reflux. Flash column chromatography (silica
gel, 70% hexane/AcOEt) afforded 10a (157 mg, 64%) as a white solid:
(s, 1H), 6.96–7.28 (m, 5H). 13C NMR (75.47 MHz, CDCl3):
d
¼13.5,
21.1, 28.9, 32.7, 35.7, 50.7, 56.0, 56.2, 63.6, 66.6, 107.9, 112.0, 127.4,
128.0, 128.2, 128.3, 130.4, 135.9, 147.1, 148.1, 171.4, 172.9. LRMS (EI,
70 eV): m/z (%)¼424 (Mþþ1, 5), 423 (Mþ, 20), 422 (15), 409 (28),
408 (Mþꢀ15, 100), 273 (5), 258 (25), 91 (21), 85 (15), 83 (26), 71 (8),
57 (11), 55 (9). C25H29NO5: calcd C 70.90, H 6.90, N 3.31; found C
70.58, H 7.05, N 3.26.
mp (AcOEt) 185–186 ꢁC. IR (KBr)
(300 MHz, CDCl3):
J¼15.6, 11.1, 5.5 Hz, 1H), 3.02–3.14 (m, 1H), 3.41 (dd, J¼11.1, 2.0 Hz,
1H), 3.56 (s, 3H,), 3.84 (s, 3H), 3.86 (s, 3H), 4.02 (d, J¼11.1 Hz, 1H),
4.23–4.30 (m, 1H), 4.29 (d, J¼2.0 Hz, 1H), 5.18 (s, 2H), 6.59 (s, 1H),
6.65 (s, 1H), 7.28–7.39 (m, 5H); 13C NMR (75.47 MHz, CDCl3):
n
¼1755, 1700 cmꢀ1
.
1H NMR
d
¼1.65 (s, 3H), 2.63–2.70 (m, 1H), 2.89 (ddd,
4.10.2. (1SR,2RS,10bSR)-2-Allyl-2-benzyloxycarbonyl-8,9-
dimethoxy-1,10b-dimethyl-1,5,6,10b-tetrahydropyrrolo[2,1-
a]isoquinolin-3-one (9b) and (1SR,2SR,10bSR)-2-allyl-2-
benzyloxycarbonyl-8,9-dimethoxy-1,10b-dimethyl-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinolin-3-one (9b0)
d
¼23.5, 28.4, 35.4, 38.5, 47.5, 51.5, 53.9, 55.8, 56.3, 61.6, 67.6, 106.9,
112.2, 114.8, 125.3, 132.3, 135.1, 127.9, 128.1, 128.4, 148.1, 148.5, 164.7,
165.0,168.2. LRMS (EI, 70 eV): m/z (%)¼492 (Mþ, 2), 477 (Mþꢀ15, 2),
393 (13), 380 (23), 379 (25), 378 (100), 350 (8), 322 (27), 284 (10),
246 (20), 245 (21), 244 (53),149 (8),105 (14), 97 (12), 92 (9), 91 (95),
85 (21), 83 (18), 79 (12), 77 (12), 71(24), 69 (19), 68 (31), 67 (10), 65
(12), 59 (41), 57 (42), 55 (26). C27H28N2O7: calcd C 65.84, H 5.73, N
5.69; found: C 65.45, H 5.50, N 5.40.
According to the general procedure, a solution of 4a (151 mg,
0.4 mmol) in dry THF (10 mL) was treated with the organocuprate,
prepared from CuI (220 mg, 1.1 mmol) and MeLi (1.43 mL of a 1.6 M
solution in hexanes, 2.3 mmol) and quenched by addition of
CH2]CHCH2I (0.04 mL, 0.5 mmol). Flash column chromatography
(silica gel, 70% hexane/AcOEt) afforded a diastereomeric mixture of
9b and 9b0 in an 80:20 diastereomeric ratio (83 mg, 50%). Both
diastereomers were separated by chromatography and character-
ized separately. Major diastereomer 9b, oil (67 mg, 40%): IR (KBr)
4.11.2. (1RS,2SR,10bSR)-2-Benzyloxycarbonyl-10b-butyl-1-
(cyanomethoxycarbonylmethyl)-8,9-dimethoxy-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinolin-3-one (10b)
According to the general procedure, 4b (207 mg, 0.5 mmol)
was treated with a solution of NaNH2 (20 mg, 0.5 mmol), DMPU
(1.3 mL, 10.9 mmol) and methyl cyanoacetate (0.1 mL, 1.0 mmol)
in dry THF (15 mL) for 3 h under reflux. Flash column chroma-
tography (silica gel, 70% hexane/AcOEt) afforded 10b (141 mg,
n
¼1730, 1686 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
¼1.20 (d, J¼7.1 Hz,
3H), 1.39 (s, 3H), 2.44 (q, J¼7.1 Hz, 1H), 2.52–2.88 (m, 4H), 3.02–
3.14 (m, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 4.40 (dd, J¼13.1, 4.7 Hz, 1H),
4.94–5.04 (m, 2H), 5.12 (d, J¼12.3 Hz, 1H), 5.30 (d, J¼12.3 Hz, 1H),
5.51–5.67 (m, 1H), 6.53 (s, 1H), 6.61 (s, 1H), 7.26–7.39 (m, 5H). 13C
NMR (75.47 MHz, CDCl3):
55.9, 59.8, 61.9, 67.0, 107.3, 111.6, 119.9, 124.4, 128.4, 128.5, 128.7,
d
¼11.8, 23.0, 29.0, 37.9, 35.2, 45.2, 55.7,
64%yield, 76% conversion) as an oil: IR (KBr)
n
¼1750, 1692 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
¼0.82 (t, J¼7.1 Hz, 3H), 1.01–1.40 (m,
132.7, 135.2, 135.6, 147.7, 147.7, 169.3, 171.0. LRMS (EI, 70 eV): m/z
4H), 1.97–2.03 (m, 2H), 2.64 (dd, J¼13.9, 2.0 Hz, 1H), 2.76–2.89 (m,

5796
C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
1H), 2.97–3.09 (m, 1H), 3.22 (dd, J¼11.9, 2.0 Hz, 1H), 3.53 (s, 3H),
3.84 (s, 3H), 3.86 (s, 3H), 4.06 (d, J¼11.9 Hz, 1H), 4.23 (d, J¼2.0 Hz,
1H), 4.40 (dd, J¼12.9, 4.2 Hz, 1H), 5.18 (d, J¼2.0 Hz, 2H), 6.59 (s,
1H), 6.65 (s, 1H), 7.26–7.40 (m, 5H); 13C NMR (75.47 MHz, CDCl3):
NMR (75.47 MHz, CDCl3):
d
¼13.7, 22.9, 27.3, 28.4, 37.9, 45.8, 47.4,
51.8, 52.1, 52.5, 52.7, 55.8, 56.2, 66.2, 67.4, 109.5, 111.4, 126.5, 128.2,
128.8, 128.3, 128.5, 135.5, 147.9, 148.1, 166.8, 167.9, 168.6, 169.8.
LRMS (EI, 70 eV): m/z (%)¼567 (Mþ, 1), 511 (33), 510 (100), 420 (24),
403 (14), 402 (58), 401 (12), 376 (28), 374 (24), 342 (36), 379 (24),
378 (93), 316 (22), 24 (43), 91 (70), 57 (10). C31H37NO9: calcd C
65.59, H 6.57, N 2.47; found: C 65.62, H 6.59, N 2.46.
d
¼13.7, 22.9, 27.1, 29.4, 37.2, 38.0, 37.5, 49.5, 51.7, 53.9, 55.8, 56.4,
64.6, 67.7, 106.9, 112.6, 114.6, 126.5, 129.7, 135.2, 127.9, 128.2, 128.5,
148.2, 148.5, 165.0, 166.4, 168.4. LRMS (EI, 70 eV): m/z (%)¼535
(Mþþ1, 4), 534 (Mþ, 10), 478 (30), 477 (Mþꢀ57, 100), 379 (22), 378
(84), 342 (20), 316 (35), 284 (7), 245 (8), 244 (33), 91 (62), 59 (8).
C30H34N2O7: calcd C 67.40, H 6.41, N 5.24; found: C 67.44, H 6.43, N
5.26.
4.12. (1RS,2RS,10bSR)-2-Benzylcarbonyl-1-(1,1,1,3,3,3-
hexamethyldisilazan-2-yl)-10b-methyl-8,9-dimethoxy-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (12)
4.11.3. (1SR,2RS,10bSR)-2-Benzyloxycarbonyl-1-
[bis(methoxycarbonyl)methyl]-8,9-dimethoxy-10b-
methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
A solution of lactam 4a (110 mg, 0.28 mmol) in dry THF (5 mL)
was added via canola to a solution of LiHMDS (0.4 mL of a 0.7 M
solution in hexanes, 0.28 mmol) at ꢀ78 ꢁC. After 10 min, the re-
action mixture was allowed to reach rt and stirred at this temper-
ature for 24 h. Then the reaction was quenched by addition of 12%
NH4OH (10 mL). The organic layer was separated, and the aqueous
phase was extracted with Et2O (1ꢂ10 mL) and CH2Cl2 (3ꢂ15 mL).
The combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. Column chromatography (silicagel, MeOH/CHCl3
96%) afforded pyrroloisoquinolone 12 (114 mg, 71%) as a single
3-one (11c) and (1RS,2SR,10bSR)-2-benzyloxycarbonyl-1-
[bis(methoxycarbonyl)methyl]-8,9-dimethoxy-10b-methyl-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one (10c)
According to the general procedure, 4a (100 mg, 0.25 mmol)
was treated with a solution of NaNH2 (10 mg, 0.25 mmol), DMPU
(0.4 mL, 3.3 mmol) and dimethyl malonate (0.06 mL, 0.5 mmol) in
dry THF (10 mL) for 4 h under reflux. Flash column chromatography
(silica gel, 70% hexane/AcOEt) afforded a diastereomeric mixture of
11c and 10c in an 80:20 diastereomeric ratio (81 mg, 61%). Both
diastereomers were separated by chromatography and character-
ized separately. Major diastereomer 11c, oil (65 mg, 49%): IR (KBr)
diastereomer: oil; IR (KBr)
CDCl3):
n
¼1740, 1694 cmꢀ1. 1H NMR (300 MHz,
d
¼ꢀ0.12 (s, 6H), ꢀ0.08 (s, 3H), 0.35 (s, 6H), 0.40 (s, 3H), 1.61
(s, 3H), 2.56–2.62 (m, 1H), 2.84–2,91 (m, 2H), 3.86–3.93 (m, 1H),
3.86 (s, 3H), 3.87 (s, 3H), 4.10 (d, J¼11.1, Hz, 1H), 4.35–4.41 (m, 1H),
5.19 (d, J¼4.8, Hz, 2H), 6.58 (s, 1H), 6.78 (s, 1H), 7.33–7.34 (m, 5H).
n
¼1750, 1692 cmꢀ1. 1H NMR (300 MHz, CDCl3):
¼1.66 (s, 3H), 2.49
d
(dd, J¼15.5, 2.2 Hz, 1H), 2.72 (ddd, J¼15.5, 12.3, 5.1 Hz, 1H), 2.92
(ddd, J¼12.6, 12.3, 3.6 Hz, 1H), 3.25 (s, 3H), 3.47–3.50 (m, 4H), 3.67
(d, J¼3.9 Hz, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 3.92 (d, J¼1.9 Hz, 1H),
4.33 (dd, J¼12.7, 5.1 Hz, 1H), 5.18 (d, J¼12.3 Hz, 1H), 5.27 (d,
J¼12.3 Hz, 1H), 6.50 (s, 1H), 6.51 (s, 1H), 7.28–7.41 (m, 5H). 13C NMR
13C NMR (75.47 MHz, CDCl3):
d
¼3.1, 5.6, 24.0, 29.3, 35.0, 55.2, 55.7,
56.3, 63.8, 67.0, 67.4, 110.2, 111.8, 125.6, 128.1, 128.2, 128.4, 131.5,
135.3, 147.3, 147.9, 166.8, 169.6. LRMS (EI, 70 eV): m/z (%)¼555
(Mþþ1, 5), 554 (Mþ, 12), 539 (6), 455 (8), 378 (22), 364 (19), 306
(15), 262 (8), 258 (11), 244 (11), 214 (13), 206 (47), 205 (100), 204
(9), 190 (12), 146 (14), 130 (8), 100 (7), 99 (6), 91 (63), 79 (5), 77 (5),
73 (39), 65 (5). C29H42N2O5Si2: calcd C 62.78, H 7.63, N 5.05; found:
C 62.49, H 7.46, N 5.12.
(75.47 MHz, CDCl3):
d¼28.4, 31.0, 35.4, 46.7, 51.8, 52.4, 52.7, 55.8,
56.2, 63.1, 67.3, 109.8, 111.4, 127.5, 128.1, 128.4, 128.5, 135.5, 147.8,
148.1, 166.3, 166.7, 168.4, 169.7. LRMS (EI, 70 eV): m/z (%)¼526
(Mþþ1, 9), 525 (Mþ, 5), 511 (31), 510 (99), 434 (12), 403 (12), 402
(52), 401 (13), 374 (28), 342 (31), 244 (43), 206 (10), 107 (10), 91
(100), 65 (13), 59 (10). C28H31NO9: calcd C 63.99, H 5.94, N 2.66;
found: C 63.97, H 5.97, N 2.68. Minor diastereomer 10c, oil (16 mg,
4.13. (1SR,2SR,10bSR)-1-Benzylamino-2-N-benzylcarbamoyl-
10b-methyl-8,9-dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-
a]isoquinolin-3-one (13)
12%): IR (KBr)
d
n
¼1739, 1692 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
¼1.46 (s, 3H), 2.57–2.62 (m,1H), 2.86–3.08 (m, 2H), 3.56 (dd, J¼9.5,
Benzylamine (0.04 mL, 0.4 mmol) and water (0.02 mL,
1.0 mmol) were added drop wise over lactam 4d (80 mg, 0.2 mmol)
at rt and the reaction mixture was stirred for 18 h. Crystallization
from ethyl acetate afforded 13a (71 mg, 72%) as a white solid: mp
5.1 Hz, 1H), 3.61 (s, 3H), 3.71 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 4.07
(d, J¼5.1 Hz, 1H), 4.16 (d, J¼15.5 Hz, 1H), 4.23–4.36 (m, 1H), 5.14 (s,
2H), 6.54 (s, 1H), 6.74 (s, 1H), 7.27–7.31 (m, 5H). 13C NMR
(75.47 MHz, CDCl3):
d
¼23.8, 28.5, 35.5, 46.6, 50.8, 51.1, 52.9, 53.0,
(AcOEt) 125–126 ꢁC. IR (KBr)
(300 MHz, CDCl3):
n
¼3300, 1690, 1660 cmꢀ1
.
1H NMR
55.7, 56.1, 62.5, 67.2, 107.7, 111.9, 125.3, 127.9, 128.3, 132.8, 135.4,
147.8, 148.0, 166.8, 168.2, 169.0. LRMS (EI, 70 eV): m/z (%)¼526
(Mþþ1, 19), 525 (Mþ, 34), 511 (11), 510 (36), 434 (13), 403 (7), 402
(32), 401 (8), 379 (11), 374 (18), 344 (10), 342 (21), 244 (31), 206
(28), 107 (11), 91 (100), 65 (13), 59 (9). C28H31NO9: calcd C 63.99, H
5.94, N 2.66; found: C 63.94, H 5.96, N 2.69.
d
¼1.55 (s, 3H), 1.55–1.64 (br s, 1H), 2.67 (dd,
J¼15.7, 3.4 Hz, 1H), 2.82–2.96 (m, 1H), 3.08 (td, J¼12.7, 4.0 Hz, 1H),
3.23 (d, J¼10.3 Hz, 1H), 3.69 (s, 3H), 3.82 (d, J¼10.3 Hz, 1H), 3.84 (s,
3H), 3.92 (d, J¼13.5 Hz, 1H), 4.33 (d, J¼13.5 Hz, 1H), 4.30–4.36 (m,
1H), 4.45 (dd, J¼15.0, 5.5 Hz, 1H), 4.58 (dd, J¼15.0, 6.1 Hz, 1H), 6.54
(s, 1H), 7.22–7.46 (m, 11H), 7.81 (t, J¼5.5 Hz, 1H). 13C NMR
(75.47 MHz, CDCl3):
d
¼22.6, 28.3, 34.7, 43.5, 53.4, 53.9, 55.8, 61.3,
4.11.4. (1SR,2RS,10bSR)-2-Benzyloxycarbonyl-1-[bis(methoxy-
carbonyl)methyl]-10b-butyl-8,9-dimethoxy-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinolin-3-one (11d)
According to the general procedure, 3b (105 mg, 0.24 mmol)
was treated with a solution of NaNH2 (9.44 mg, 0.24 mmol), DMPU
(0.38 mL, 3.15 mmol) and dimethyl malonate (0.05 mL, 0.48 mmol)
in dry THF (5 mL) for 6 h under reflux. Flash column chromato-
graphy (silica gel, 70% hexane/AcOEt) afforded 11d (62 mg, 51%
65.9, 107.8, 111.0, 123.6, 126.9, 127.3, 127.5, 127.6, 128.3, 128.6, 133.4,
138.0, 140.8, 147.8, 147.9, 167.1, 167.8. LRMS (EI, 70 eV): m/z (%)¼499
(Mþ, 3), 485 (22), 484 (67), 377 (40), 272 (35), 245 (25), 244 (15),
115 (9), 107 (18), 99 (11), 97 (23), 91 (36), 77 (6). C30H33N3O4: calcd
C 72.12, H 6.66, N 8.41; found: C 72.33, H 6.82, N 8.34.
4.14. (10bR)-(D)-2-[(1S,2R,4R,SR)-(2-Hydroxy-7,7-dimethyl-
bicyclo[2.2.1]heptan-1-yl)methylsulfinyl]-8,9-dimethoxy-
10b-methyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-one
[(10bR)-15]
yield, 90% conversion) as an oil: IR (KBr)
NMR (300 MHz, CDCl3):
1.90–2.16 (m, 2H), 2.33–2.67 (m, 1H), 2.70–2.97 (m, 1H), 3.01–3.26
(m, 1H), 3.27 (s, 3H), 3.41–3.50 (m, 1H), 3.51 (s, 3H), 3.61 (d,
J¼4.3 Hz, 1H), 3.85 (s, 3H), 3.86 (s, 3H), 3.93–3.95 (m, 1H), 4.41 (dd,
J¼12.3, 5.5 Hz, 1H), 5.24 (s, 2H), 6.63 (s, 2H), 7.25–7.43 (m, 5H). 13C
n
¼1735, 1690 cmꢀ1
.
1H
d
¼0.74 (t, J¼6.7 Hz, 3H), 0.77–1.40 (m, 4H),
A
solution of isoindoloisoquinoline (10bR)-149b (84 mg,
0.16 mmol) in o-DCB (5 mL) was refluxed for 24 h. The evolution of
the reaction was monitored by 1H NMR. The crude product was

C. Camarero et al. / Tetrahedron 65 (2009) 5787–5798
5797
purified by column chromatography (silica gel, 98% ethyl acetate/
NEt3) to afford dihydropyrroloisoquinoline (10bR)-15 (33 mg, 54%)
of a 1 M solution). Ethyl ether (5 mL) was added, the organic layer
was separated and the aqueous phase was extracted with CHCl3
(3ꢂ10 mL). The combined organic extracts were washed with sat-
urated Na2S2O3 (3ꢂ10 mL) and brine (3ꢂ10 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by flash column chroma-
23
as a white solid: mp (pentane) 109–110 ꢁC; [
a
]
þ99.8 (c 0.5,
D
CHCl3). The enantiomeric excess determined on the corresponding
desulfinylated product [(10bR)-(þ)-8,9-dimethoxy-10b-methyl-
5,6-dihydropyrrolo[2,1-a]isoquinolin-3-one9b] by CSP HPLC was
>99% by comparison with the racemic mixture. Chiralcel OD, 20%
hexane/2-propanol, 0.4 mL/min; tR [(10bR)]¼23.2 min (>99%);
tography (silicagel, AcOEt) afforded tetrahydropyrroloisoquinoline
23
(1R,10bR)-7 (18.5 mg, 56%) as an oil: [
a]
þ109.0 (c 0.1, CHCl3). The
D
enantiomeric excess determined by CSP HPLC was >99% by
comparison with the racemic mixture. Chiralcel OD, 10% hexane/2-
propanol, 0.4 mL/min; tR [(1R,10bR)-7]¼41.4 min (> 99%);
tR[(1S,10bS)-7]¼46.7 min (<1%). The spectroscopic data were
identical to those reported for the racemate.
tR[(10bS)]¼21.9 min (<1%): IR (KBr)
n
¼3482, 1676, 1010 cmꢀ1
.
1H
NMR (300 MHz, CDCl3):
d
¼0.86 (s, 3H), 1.03–1.07 (m, 2H), 1.07 (s,
3H), 1.20–1.31 (m, 1H), 1.49–1.56 (m, 1H), 1.59 (s, 3H), 1.65–1.81 (m,
3H), 2.67 (dd, J¼16.1, 4.0 Hz, 1H), 2.81 (d, J¼11.0 Hz, 1H), 2.88–3.00
(m, 1H), 3.06 (d, J¼11.0 Hz, 1H), 3.22–3.27 (m, 2H), 3.83 (s, 3H),
3.90 (s, 3H), 3.95–3.97 (m, 1H), 4.43 (dd, J¼13.2, 6.4 Hz, 1H), 6.59
(s, 1H), 6.71 (s, 1H) 6.99 (s, 1H); 13C NMR (75.47 MHz, CDCl3):
Acknowledgements
d
¼20.0, 20.7, 27.1, 27.2, 29.3, 30.4, 31.2, 35.1, 39.2, 45.2, 47.7, 51.8,
Financial support from MICINN (CTQ2006-01903), Gobierno
55.8, 56.2, 64.4, 76.1, 109.1, 111.9, 124.9, 129.3, 133.6, 144.3, 147.7,
148.2, 167.4. LRMS (EI, 70 eV): m/z (%)¼459 (Mþ, <1), 127 (6), 125
(6), 113 (7), 111 (9), 99 (10), 98 (6), 97 (15), 95 (7), 86 (9), 85 (62),
84 (8), 83 (100), 82 (7), 81 (9), 71 (35), 70 (18), 69 (33), 67 (12), 57
(77), 56 (14), 55 (51). C25H33NO5S: calcd C 65.33, H 7.24, N 3.05;
found: C 65.63, H 7.48, N 2.95.
´
Vasco (GIC07/92-IT-227-07), and Universidad del Paıs Vasco is
gratefully acknowledged.
References and notes
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isoquinolines, see: Mikhailovskii, A. G.; Shklyaev, V. S. Chem. Heterocycl. Comp.
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4.15. (1R,2R,10bR)-(+)-2-(2-Hydroxy-7,7-dimethyl-
bicyclo[2.2.1]heptan-1-ylmethylsulfinyl)-8,9-dimethoxy-
1,10b-dimethyl-1,5,6,10b-tetrahydropyrrolo[2,1-
a]isoquinolin-3-one [(1R,2R,10bR)-16]
Methylmagnesium chloride (1.01 mL of a 3.0 M solution in THF,
3.04 mmol) was added drop wise over a suspension of CuI (289 mg,
1.52 mmol) in dry THF (7 mL) at ꢀ20 ꢁC. After 15 min, the mixture
was cooled to ꢀ78 ꢁC, and a solution of lactam 15 (70 mg, 0.15 mmol)
and TMSCl (0.04 mL, 0.30 mmol) in dry THF (3 mL) was added. The
reaction mixture was allowed to warm up to 0 ꢁC, and stirred at this
temperature for 16 h. The reaction was quenched by sequential ad-
dition of NH4OH (12% aq) (20 mL) and NH4Cl (satd) (10 mL) at 0 ꢁC.
After allowing the mixture to warm up to rt, the organic layer was
separated, and the aqueous phase was extracted with CH2Cl2
(3ꢂ15 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Flash column chromatography (silicagel, 70%
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Chem. 1982, 47, 513–517; Protoberberines; (c) Cobas, A.; Guitian, E.; Castedo, L. J.
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hexane/AcOEt, 2% NEt3) afforded tetrahydropyrroloisoquinolone
23
(1R,2R,10bR)-16 (41 mg, 56%) as an oil: [
a
]
þ131.3 (c 0.5, CHCl3). The
D
enantiomeric excess was determined on the corresponding desulfi-
nylated product (see below). IR (KBr)
(300 MHz, CDCl3):
n
¼3422, 1675 cmꢀ1. 1H NMR
d
¼0.73 (s, 3H), 0.97 (s, 3H),1.01–1.09 (m,1H),1.13–
1.25 (m, 1H), 1.39–1.47 (m, 1H), 1.43 (s, 3H), 1.50 (d, J¼6.7 Hz, 3H),
1.57–1.79 (m, 4H), 2.15–2.20 (m, 2H), 2.49 (d, J¼10.7 Hz,1H), 2.67 (dd,
J¼16.0, 2.1 Hz, 1H), 2.78–2.84 (m, 1H), 2.98–3.04 (m, 1H), 3.21 (d,
J¼11.7 Hz,1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.03–4.06 (m, 1H), 4.31 (br s,
1H), 4.42 (dd, J¼12.8, 5.4 Hz, 1H), 6.60 (s, 1H), 6.75 (s, 1H). 13C NMR
(75.47 MHz, CDCl3):
d
¼13.1,19.8, 20.6, 22.0, 27.1, 29.5, 29.9, 35.3, 38.7,
45.0, 46.1, 47.4, 51.8, 53.4, 55.8, 56.1, 61.6, 75.8, 108.0, 111.9, 125.0,
133.4,147.8,147.9,169.7. LRMS (EI, 70 eV): m/z (%)¼459 (Mþ, <1),127
(6), 125 (6), 113 (7), 111 (9), 99 (10), 98 (6), 97 (15), 95 (7), 86 (9), 85
(62), 84 (8), 83 (100), 82 (7), 81 (9), 71 (35), 70 (18), 69 (33), 67 (12),
57 (77), 56 (14), 55 (51). C26H37NO5S: calcd C 65.65, H 7.84, N 2.94;
found: C 65.89, H 7.96, N 2.83.
4.16. (1R,10bR)-(D)-8,9-Dimethoxy-1,10b-dimethyl-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinolin-3-one [(1R, 10bR)-7]
To a solution of (1R,10bR)-16 (57 mg, 0.12 mmol) in dry THF
(3 mL), t-BuOH (0.11 mL, 1.12 mmol), SmI2 (12 mL of a 0.1 M solu-
tion in THF, 1.12 mmol), and HMPA (1.41 mL, 8.32 mmol) were
added sequentially at rt. The resulting mixture was stirred at this
temperature for 2 h and quenched by the addition of cold HCl (5 mL

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