10b-Substituted hexahydropyrrolo-isoquinolines: Studies on diastereoselective formation of a quaternary carbon stereocenter via N-acyliminium ion cyclization

Article abstract of DOI:10.1016/j.tet.2005.10.028

The stereoselective synthesis of hexahydro-pyrroloisoquinolines with a quaternary carbon stereocenter is described. The presented methodology employs the addition of a Grignard reagent to the carbonyl group of imide 1, derived from l-tartaric acid, followed by acetylation and BF₃·Et ₂O induced cyclization. The acetylation-cyclization sequence can be run either as a one-pot process, or stepwise in a selected solvents. The crucial step, an acid-catalyzed carbon-carbon bond-forming reaction via an N-acyliminium ion offers high stereoselectivity, which has been shown to be strongly dependent on the size of the R¹ substituents and the reaction conditions, that is, choice of solvent, amount of a Lewis acid, temperature, and concentration of the substrate. Based on the results observed, participation of solvent in the cyclization, via an N-acyliminium cation is proposed.

Full text of DOI:10.1016/j.tet.2005.10.028

Tetrahedron 62 (2006) 943–953
10b-Substituted hexahydropyrrolo-isoquinolines: studies
on diastereoselective formation of a quaternary carbon
stereocenter via N-acyliminium ion cyclization
*
Zbigniew Kałuz˙a, Danuta Mostowicz, Grzegorz Dołe˛ga, Katarzyna Mroczko
´
and Robert Wojcik
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warszawa, Poland
Received 2 August 2005; revised 29 September 2005; accepted 13 October 2005
Available online 8 November 2005
Abstract—The stereoselective synthesis of hexahydro-pyrroloisoquinolines with a quaternary carbon stereocenter is described. The
presented methodology employs the addition of a Grignard reagent to the carbonyl group of imide 1, derived from L-tartaric acid, followed by
acetylation and BF3$Et2O induced cyclization. The acetylation–cyclization sequence can be run either as a one-pot process, or stepwise in a
selected solvents. The crucial step, an acid-catalyzed carbon–carbon bond-forming reaction via an N-acyliminium ion offers high
stereoselectivity, which has been shown to be strongly dependent on the size of the R1 substituents and the reaction conditions, that is, choice
of solvent, amount of a Lewis acid, temperature, and concentration of the substrate. Based on the results observed, participation of solvent in
the cyclization, via an N-acyliminium cation is proposed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
cyclization sequence (Scheme 1). Herein we detail the
utility of this methodology and disclose further findings that
the reaction conditions, that is, choice of solvent, amount of
a Lewis acid, temperature, and even concentration of the
substrate, have a great impact on the stereoselectivity of an
N-acyliminium ion cyclization, the key step of the synthesis
of 10b-substituted hexahydropyrrolo-isoquinolines.
The numerous syntheses of chiral, nitrogen-containing
heterocycles that involve an iminium ion cyclization in
the construction of a new stereogenic center are widely
reported.1,2 The isoquinoline3 and pyrrolo[2,1-a]isoqui-
noline4 alkaloids with significant bioactivity often have
the stereocenters located at the tertiary or quaternary carbon
atom, in the a-nitrogen position. Consequently, iminium ion
chemistry is widely utilized in preparation of such
compounds.5 The asymmetric construction of a quaternary
carbon stereocenter, frequently present in a variety of
naturally occurring products, is a challenging task by itself.
During the last decade, special attention has been paid to the
development of both catalytic6 and non-catalytic7 methods
for the asymmetric synthesis of compounds containing
carbon atoms with four different non-hydrogen substituents.
2. Results and discussion
A preliminary study on the preparation of pyrroloiso-
quinolines 4a–f from imide 1, derived from L-tartaric acid,
was carried out employing procedure analogous to that
reported by Lete and co-workers5f–g (Scheme 1). The
nucleophilic addition of a Grignard reagent to the carbonyl
groupof1ledtohydroxylactam2a–f, which,incaseof2a, was
isolatedandanalysed. However, wefound thattheuseofcrude
reaction product directly in the next step was more practical.
Hydroxylactam2a, subjectedtothecyclizationinthepresence
of trifluoroacetic acid in dichloromethane at reflux,9 led to the
expected 5a in a trace amounts only. Changing of the reaction
conditions, that is, solvent, temperature, time, protic and/or
Lewis acid did not improve the yield of 5a.
We have recently described the stereocontrolled synthesis
of hexahydro-pyrrolo[2,1-a]isoquinolines that contain a
quaternary carbon stereocenter.8 Our methodology employs
the addition of a Grignard reagent to imide 1, derived
from L-tartaric acid, followed by the one-pot acetylation–
Keywords: N-Acyliminium ion cyclization; Diastereoselective synthesis;
Isoquinoline alkaloids.
We assumed that acetylation of the hydroxyl group of 2a
would increase the rate of the slowest step of the reaction,
*
Corresponding author. Tel.: C48 22 343 2142; fax: C48 22 632 6681;
e-mail: zkicho@icho.edu.pl
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.028

944
Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
AcO
AcO
TMSO
TMSO
TMSO
TMSO
AcO
AcO
R1
R
OH
R1
OAc
R1
O
R
a
c
b
N
N
N
N
N
R
R
O
O
O
O
2a: R1= Ph
2b: R1= Me
3a-3f
1
AcO
R1
R
OMe
2c: R1=
R=
Ph
AcO
OMe
2d: R1= c-Hexyl
2e: R1= i-Pr
O
2f: R1= Vinyl
OMe
OMe
OMe
OMe
e
OMe
OMe
R1
N
R1
R1
10b
HO
TBSO
HO
HO
AcO
d
AcO
N
N
O
O
O
5a-f(S),(R)
6a-f(S),(R)
4a-f(S),(R)
R1=
f
Ph
S
R
= 10b(S) epimer
= 10b(R) epimer
OMe
OMe
Ph
Ph
OMe
OMe
O
OH
O
(R)
(S)
HO
N
N
O
7(R)
O
7(S)
Scheme 1. Reagents and conditions: (a) R1MgBr (1.5 equiv), THF, 0 8C gradually to rt, 1–2 h; (b) Ac2O (4 equiv), DMAP (1.1 equiv), MeCN or Me2CO rt,
3–4 h; (c) BF3$Et2O (4 equiv), rt, 10 min then semi-satd aq NaHCO3; (d) MeONa, MeOH; (e) TBS-Cl, imidazole, DMF, rt, 24 h; (f) Pd(OAc)2 (0.2 equiv),
TEA, THF, rt, 2 h.
namely the N-acyliminium ion formation,10 thus facilitating
the subsequent cyclization. Treatment of 2a with acetic
anhydride and DMAP in acetonitrile gave unstable
triacetate 3a, which was isolated by the chromatography
on silica gel in only a 15% yield. Consequently, the crude
triacetate 3a in acetonitrile was treated with BF3$Et2O to
give hexahydro-pyrroloisoquinolines 4a(S) and 4a(R) in a
3:1 ratio, respectively. Several other 10b-substituted
pyrroloisoquinolines 4b–f(S),(R) were obtained as a mixture
of diastereoisomers, utilizing the modified procedure
consisting of addition of Grignard reagent to the imide 1
followed by the one-pot acetylation–cyclization of crude
2a–f. The results are summarized in Table 1. The overall
yields of 4a–f(S),(R), based on the starting imide 1, were
high, except for entry 6. Although the 10b-epimers
4a–f(S),(R) or their respective dihydroxy derivatives
5a–f(S),(R) can be separated by tedious chromatography
on silica gel, we have found that the respective 2-t-
butyldimethylsilyloxy-pyrroloisoquinolines 6a–f(S),(R) are
much easier to purify due to the improved differentiation of
the polarity of the 10b epimers. The alkaline hydrolysis of
the acetates 4a–f(S),(R) followed by the silylation of the
crude diols and separation of the resulting 2-silylethers gave
optically pure pyrroloisoquinolines 6a–f(S) and 6a–f(R) in a
high yield (Scheme 1, Table 1). The assignment of the
configuration at the bridgehead carbon atom C-10b in
pyrroloisoquinolines 4a–f(S),(R) can be accomplished by
NOESY experiment carried out with the mixture of
diastereomers. However, due to the overlapping of the
signals of epimers, only selected data of the major
component can be collected and analysed, which may lead
to some degree of uncertainty over data interpretation. The
isolation of pure 6a–f(S) and 6a–f(R) allowed for an easy
and unequivocal assignment of the configuration at C-10b of
the obtained pyrroloisoquinolines.
The NOESY experiments, carried out with 6a–b,d–f(S)
showed an interaction between protons of the R1 substituent
(both a and b) at the C-10b-position with protons at C-2 and
the OH group, as exemplified for 6f(S) (Fig. 1). For the
Table 1. Stereocontrolled synthesis of hexahydro-pyrroloisoquinolines 4a–f(S),(R) and separation of diastereomers as an optically pure 2-silyloxy-derivatives
6a–f(S),(R)a
Entry
R1
4(S),(R) Yield (%)b
S:Rc
6(S) Yield (%)d
6(R) Yield (%)d
1
2
3
4
5
6
Ph
Me
PhC^C
c-Hexyl
i-Pr
82
85
81
50
80
38
3:1
71
61
68
6.5
10
60
23
11
7.4
74
67
13
5.6:1
9.5:1
1:10
1:6.3
4.6:1
Vinyl
a General procedure A, for details see Section 4.
b Isolated yields of the mixture of diastereomers calculated for three-steps starting from 1.
c Diastereomeric ratio was determined by 1H NMR analysis.
d Isolated yields of pure diastereomers calculated for two-steps starting from 4.

Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
945
Me
of 10b(R) epimers, which is indicated by a small J1,2 values
(0–3.1 Hz).
Me
Me
Me
O
O
3.0
H
0.5
H
5.0
O
5.3 7.3
O
H
H
5.2
6.8
5.3
Our observation that the values of J1,2 coupling constants of
all 10b(S) epimers 4a–f and 6a–f are large (6.8–8.3 Hz) and
the respective values of compounds 10b(R) series are small
(3.1–0.0 Hz) confirmed the above assignment. In addition,
this regularity can be used as a rule for easy determination of
the configuration at C-10b of pyrroloisoquinolines of this
structure.
H
H
10
10
HO
HO
2.7
3.1
H
H
1
1
10b (R)
10b (S)
2
2
6
6
TBSO
TBSO
3
N
3
N
4
5
5
4
O
O
6f(R)
6f(S)
Figure 1.
The unequivocal assignment of the configuration at C-10b for
all pyrroloisoquinolines 4a–f allowedfor the rationalization of
the observed stereoselectivity of cyclization reaction
(Table 1). The plausible transition state of the cyclization is
depicted on Figure 2. The internal nucleophile (dimethox-
yphenyl moiety) may approach the N-acyliminium ion A
either anti- or syn- with respect to the acetoxy group involved
in the bridging of adjacent cationic center.12 The diastereomer
C-10b(S) and C-10b(R) is a product of anti- and syn-addition
of the nucleophile, respectively.
C-10bR epimers, the respective protons of the R1 substituent
interact only with proton at C-1.
The 10b-phenylethynyl-substituted pyrroloisoquinolines
6c(S),(R) do not possess diagnostic protons that are able to
interact with protons at C-1 or C-2, thus it is impossible to
carry out the direct assignment of configuration at C-10b
solely on the basis of NOE experiments. However, the
b-ethynyl-substituted alcohols easily undergo cyclization to
give the respective dihydrofurans.11 The epimeric mixture
of 5c(S),(R) was subjected to the palladium-catalyzed
cyclization to give the dihydrofuranyl derivative 7(S) in
82% yield. The epimeric 7(R) compound was not detected in
the crude reaction mixture. The exclusive formation of 7(S)-
isomer indicates that the major diastereomer of 4c(S),(R)
possesses the S-configuration at the C-10b.
The stereochemical outcome of the cyclization reactions
described in this paper, can be rationalized by assuming the
importance of differences in the steric interactions of
the approaching nucleophile with the R1 substituent versus
the acetoxy group. The prevalent anti-addition of the
nucleophile was observed for relatively small R1 groups
(phenyl, methyl, vinyl, phenylethynyl, entries 1–3, 6
Table 1). In contrast, when bulky R1 groups (c-hexyl,
i-propyl, entries 4 and 5) are present, syn-addition takes
place primarily.
Careful analysis of spectroscopic data of both the
pyrroloisoquinolines 4a–f(S),(R) and respective 2-silyloxy
derivatives 6a–f(S),(R) revealed an interesting regularity in
their J1,2 values (Tables 2 and 3). The J1,2 values of 4a–f(S)
were in the range of 6.8 Hz (R1ZPh) to 8.0 Hz (R1Zi-Pr),
while the respective coupling constants of 10b(R)-series
compounds were substantially smaller: 2.7 and 2.3 Hz
(R1ZPh, c-hexyl, respectively) and 0.0 Hz for the remain-
ing compounds. The same regularity, even more pro-
nounced, was observed for the 2-silyloxy derivatives 6a–
f(S),(R) (Table 3). The J1,2 values of all 10b(S)-epimers
were 8.3 Hz, while compounds of 10b(R)-series showed J1,2
values in the range of 3.1–0.0 Hz. The large vicinal coupling
constants (w8 Hz) of pyrroloisoquinolines of 10b(S) series
indicate pseudo-equatorial arrangement of the substituents
at C1 and C2, constrained by the steric interaction of the
C-10b and C1 groups. Similar steric interactions lead to the
pseudo-axial arrangement of the substituents at C1 and C2
Our methodology of a simple, three-step synthesis of the
C-10b-substituted-1,2-diacetoxy-hexahydro-pyrrolo-isoqui-
nolines 4a–f(S),(R) offers good overall chemical yield, but
only moderate stereoselectivity. To improve the stereo-
selectivity of the key step, namely the acid-catalysed
cyclization via N-acyliminium ion, we decided to re-
investigate the reaction conditions.
The main question always associated with the nucleophilic
addition to the N-acyliminium ion derived from 3-sub-
stituted-,12,13 3,4-disubstituted-pyrrolidine14 or 3-substi-
tuted-piperdines,15 is whether to expect syn- or anti-
stereoselection in relation to the substituent adjacent to the
cationic center. In general, the stereoselection primarily
Table 2. The J1,2 coupling constants of hexahydro-pyrroloisoquinolines 4a–f(S),(R)
C-10b
R1
Ph
Me
Ph^
c-Hexyl
i-Pr
Vinyl
(S)
(R)
6.8
2.7
7.9
0
7.8
0
7.9
2.3
8.0
0
7.9
0
J1,2 (Hz)
Table 3. The J1,2 coupling constants of hexahydro-pyrroloisoquinolines 6a–f(S),(R)
C-10b
R1
Ph
Me
Ph^
c-Hexyl
i-Pr
Vinyl
(S)
(R)
8.3
3.1
8.3
0
8.3
0
8.3
2.0
8.3
2.2
8.3
0
J1,2 (Hz)

946
Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
the BF3$Et2O induced cyclization of 3a in a variety of
solvents are summarized in Table 4.
Me
N
u
O
OAc
R1
OAc
X
O
+ X
- X
O
O
O
N
N
N
The cyclization of 3a conducted in CH2Cl2 gave a mixture
of the product anti- [10b(S)] and syn-addition [10b(R)] in
the ratio of 16.1:1, respectively (entry 1). When 1,2-
dichloroethane was used the amount of anti-product
decreased substantially (10.5:1, entry 2). The change to a
more polar solvent such as acetonitrile, nitromethane, acetic
acid, tetrahydrofuran or ethyl acetate, resulted in further
decrease of anti selectivity (entries 3–10). The lowest anti
selectivity was observed in unusual solvents such as
3-pentanone, acetone and pinacolone (entries 11–13).
Although in the presence of a Lewis acid these ketones
can undergo self-condensation, it apparently did not affect
the very fast N-acyliminium cyclization.
AcO
AcO
AcO
R1
R1
X
R1
R
R
Nu
B1
C1
A
X
N
OAc
OAc
R1
O
R1
O
N
X
AcO
AcO
R
R
B2
C2
Figure 2.
depends on the C-3 substituent. Thus, the acetoxy-
substituent should induce the high anti selectivity via
neighboring group participation, while the 3-benzyloxy- or
silyloxy- derivatives should prefer the moderate syn-
addition of the nucleophile. However, the C-3 silyloxy-14b
or benzyloxy-15 substituent can induce the same level of
trans-selectivity as the acetoxy group. Recently, Kobayashi
and co-workers proposed a rationalization of this phenom-
enon by assuming a strong dependence of the stereo-
chemistry on the nucleophile steric demand.15 Additional
factors, such as choice of acid catalyst, temperature, or
solvent will usually influence the stereoselectivity to a
limited degree only. In spite of the impressive number of
reported fine syntheses based on chiral N-acyliminium ions
where syn- versus anti- stereoselection was concerned, the
reports presenting in-depth study of this important issue are
rare as far as we know.12,13e,14b,15
We believe that solvents utilized in runs 3–10 may have
stabilized the cationic center in direct competition to the
acetoxy group, via proposed structures B1, B2, or C1, C2
(Fig. 2). Consequently, the acetoxy bridge in A may become
broken, resulting in a decreased anti-stereoselection. Such
participation of a solvent in the reaction involving the
N-acyliminium cation was never before postulated, as far as
we know. However, cases of a similar solvent participation
are well documented in glycosylation reactions proceeding
via an oxonium ion.16
In the course of the work presented in the above
investigation, we have found that reliable and well-
reproducible results can be realized only when BF3$Et2O
is quickly injected via syringe directly into a vigorously
stirred solution of 3a. This observation can be rationalized
by assumption that the stereoselectivity of a fast reaction (!
10 min) depends on a concentration of the Lewis acid
catalyst. The cyclization of 3a in the presence of 1 equiv of
BF3$Et2O yielded a mixture of C-10b epimers in a ratio
S:RZ12.5:1 (Table 5, entry 1). An increase in the amount of
Lewis acid led to the improvement of anti selection, which
reached the maximum when 4 equiv of Lewis acid were
used (entry 3). Further increase of the catalyst up to 10 equiv
did not change the proportion of diastereomers significantly.
Applying a sub-molar amount of BF3$Et2O (0.3 equiv)
resulted in a sluggish reaction. In addition the substrate was
not consumed completely, even when allowing the
cyclization to run for up to 18 h. The triacetate 3a, when
treated with 4 equiv of BF3$2AcOH gave mixture of C-10b
epimers S and R in a 8.6:1 ratio, respectively (Table 5, entry
4). In comparison with the result of run 3, the reaction
catalyzed with BF3$2AcOH was slower and less selective.
The most frequently utilized solvent for reactions involving
the N-acyliminium ion is dichloromethane, while other
solvents, such as acetonitrile, toluene, diethyl ether or
formic acid are less common.12–15 For the initial evaluation
of the influence of solvent choice on the stereoselectivity of
the discussed cyclization, we selected compound 3a as the
N-acyliminium cation precursor. Due to its thermal and
chemical instability, we used crude 3a, which can be stored
for weeks in a deep-freeze (K18 to K22 8C). The results of
Table 4. BF3$Et2O promoted cyclization of 3a. The effect of solvent on the
diastereoselectivitya
Entry
Solvent
S:Rb
1
2
3
4
5
6
7
8
CH2Cl2
1,2-Dichloroethane
Toluene
Methyl pivaloate
MeNO2
MeCN
Acetic acid
Tetrahydrofuran
Methyl acetate
Ethyl acetate
3-Pentanone
Acetone
16.1:1
10.5:1
7.7:1
6.8:1
5.8:1
3.3:1
2.9:1
2.5:1
2.6:1
2.2:1
2.0:1
1.9:1
1.7:1
No reaction
Table 5. Cyclization of 3a. The effect of varying amounts of BF3$Et2O on
diastereoselectivitya
S:Rb
9
Entry
Catalyst, (equiv)
10
11
12
13
14
1
2
BF3$Et2O, 1
BF3$Et2O, 2
BF3$Et2O, 4
BF3$2AcOH, 4
BF3$Et2O, 10
12.5:1
13.6:1
16.1:1
8.6:1
Pinacolone
DMF
3
4c
5
15.9:1
a All reactions were carried out using standard procedure: crude acetate 3a
(0.1 M/solvent) obtained via procedure A or B was treated at rt with
BF3$Et2O (4 equiv), stirred for 10 min then quenched by the addition of
satd aq NaHCO3. Isolated yields were always R80%.
a Standard procedure of Table 4 was utilized, concd 3a 0.1 M/CH2Cl2, rt.
Isolated yields were always R80%.
b Diastereomeric ratio was determined by HPLC analysis.
c The cyclization required at least 30 min for completion.
b Diastereomeric ratio was determined by HPLC analysis.

Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
947
The results presented in Table 4 (entry 7) and Table 5
indicated that the acetic acid evolved during carbon–carbon
bond formation caused the decrease anti selectivity of
cyclization either via formation of a less selective catalyst
BF3$2AcOH, or by the complexation of N-acyliminium ion
in competition to the adjacent acetoxy group.
stereoselectivity was not observed in other polar solvents
such as acetic acid, ethyl acetate or acetone, supporting our
rationale.
Table 7 presents the effect of temperature on the
stereoselectivity. A decrease in the reaction temperature
from 23 to 0 8C enhanced the anti selectivity (entries 1 and
2). However, further cooling to K10 8C resulted in a
diminished selectivity, which remained unchanged for the
other reactions carried out at K20 and K40 8C. Our results
appear to be in agreement with a recent report by Wistrand,
who observed that the syn/anti-stereoselections of the
diastereoselective allylation of N-acyliminium ion at rt
and at K78 8C were nearly the same.13a
In the course of our efforts to enhance the diastereoselec-
tivity of the cyclization, we unexpectedly noticed that small
changes in the concentration of 3a in dichloromethane led to
the substantial modification of the stereoselectivity of the
reaction. Consequently, we carried out a series of
cyclization experiments varying the concentration of 3a.
The results, presented in Table 6, can be rationalized as
follows: the rate of intramolecular reaction, like the
discussed cyclization, should not depend on the concen-
tration of the iminium ion precursor. Acetic acid, evolved
during carbon–carbon bond formation, could affect the
stabilization of the cationic center competitively to the
acetoxy group as depicted in Figure 2. A reversible cation
The outcome of our optimization experiments, presented in
Tables 4–7 allows the precise definition of the reaction
conditions, which facilitate either syn or anti selectivity of
the cyclization. Thus, to emphasize the syn-addition of the
nucleophile, a solution of N-acyliminium ion precursor 3 in
a polar solvent such as ethyl acetate, acetone or pinacolone
(concentration is not important), should be treated at rt with
BF3$Et2O (1–2 equiv). In contrast, if the anti-addition
product is required, the BF3$Et2O (4 equiv) has to be added
at 0 8C into a dilute solution of 3 in such a solvent as
dichloromethane or 1,2-dichloroethane.
Table 6. Cyclization of 3a. The effect of a concentration of the substrate on
diastereoselectivitya
Entry
Concd 3a [M]/CH2Cl2
S:Rb
1
2
3
4
5
6
0.5
0.25
0.1
0.05
0.05c
0.005
7.6:1
8.9:1
12.6:1
14.8:1
11.0:1
28.6:1
In order to assess the scope of the optimized reaction
conditions, several other 10b-substituted pyrroloisoquinolines
were prepared applying procedures B and C (Table 8).
Procedure B, favoring the syn-addition, consists of the use of
crude hydroxy-lactams 2a–e in a 0.2 M acetone solution for
the one-pot acetylation–cyclization reaction sequence. The
acetone was usedas a solvent ofchoice, since itis inexpensive,
non-toxic and offers fast and clean conversion of trimethylsi-
lylated hydroxy-lactams 2a–e into respective triacetates 3a–e.
Furthermore, as evident from Table 4, entry 13, cyclization
performed in acetone yields a relatively higher than expected
proportion of syn-addition product. Procedure C, that favors
the anti-addition of the nucleophile, is based on the use of
crude triacetates 3a–e, obtained applying procedure A or B.
The cyclization step is conducted at 0 8C by treating the
0.05 M solution of 3a–e in dichloromethane with 4 equiv of
BF3$Et2O. Experiments using procedure B led to the epimeric
mixtures 4a–e (Table 8). The product of the anti-addition of
the nucleophile was obtained preferentially when small C-10b
substituents (R1ZPh, Me, PhC^C, entries 1–3) were present.
However, the values of de for the obtained products were very
low. The reverse stereoselection was observed when the bulky
R1 groups (c-Hexyl, i-Pr, entries 4 and 5) were present. The
4d(R) and 4e(R) epimers were formed predominantly in a high
de. The cyclization of triacetates 3a–e, utilizing procedure C
resulted in a remarkable increase in anti selectivity for the
small R1 (entries 1–3) and, as expected, the decrease of syn
selectivity for bulky C-10b substituents (entries 4 and 5).
a Standard procedure of Table 4 was followed, using 1.1 equiv of
BF3$Et2O, rt. Isolated yields were always R80%.
b Diastereomeric ratio was determined by HPLC analysis.
c Reaction was run in the presence of acetic acid (4 equiv).
complexation, responsible for the decreased anti-stereo-
selection, is a second-order reaction, and as such should
depend on the reactant concentration.
The above rationalization may explain why the reaction
carried out under high-dilution conditions (0.005 M, entry
6) led to a considerable improvement in anti selectivity over
the one conducted under a higher concentration (0.5 M,
entry 1). The outcome of entries 4 and 5 showed that the
presence of a small amount of cation-complexing solvent
(4 equiv of acetic acid) can decrease the anti selectivity of
the cyclization. The reported effect of concentration on the
Table 7. Cyclization of 3a. The effect of the reaction temperature on
diastereoselectivitya
Entry
Temperature
(8C)
Reaction time
(min)
S:Rb
1
2
3
4
5
23
0
K10
K20
K40
10
15
20
30
60
16.1:1
23.0:1
17.3:1
17.8:1
17.6:1
Analyzing the results of the cyclization experiments (Tables
4–8) it is possible to conclude that the syn- versus anti-
stereoselection of this process is controlled to a major extent
by the steric requirements of susbtituent R1, and the acetoxy
group forming the bridge with neighboring cationic center.
However, the choice of solvent as well as other experimen-
tal parameters can have an effect of a lesser magnitude.
a Standard procedure of Table 4 was utilized, concd 3a 0.1 M/CH2Cl2,
4 equiv of BF3$Et2O. Isolated yields were always R80%.
b Diastereomeric ratio was determined by HPLC analysis.

948
Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
Table 8. The optimized synthesis of optical pure hexahydro-pyrroloisoquinolines 4a(S), 4b(S), 6c(S), 7c(S), 5d(R), and 6e(R)
Entry
R1
Cyclization
product
Procedurea
R:Sb
Isolated product
Yield (%)c
1
2
3
4
5
Ph
4a(S),(R)
4b(S),(R)
4c(S),(R)
4d(S),(R)
4e(S),(R)
B
C
B
C
B
C
B
C
B
C
1:1.9
1:24
1:3.4
1:17.9
1:9.2
1:22
4a(S)
4b(S)
69
73
Me
PhC^C
c-Hexyl
i-Pr
6c(S), [7c(S)]
5d(R)
69, (52)
50
19:1
4.5:1
11:1
2.5:1
6e(R)
42
a Procedure B: crude hydroxylactams 2a–e were acetylated (0.2 M/acetone, DMAP 1.1 equiv, Ac2O, 4.0 equiv, rt, 3 h) and treated at rt with BF3$Et2O
(3 equiv), stirred for 15 min then quenched with satd aq NaHCO3. Procedure C: crude acetylated lactams 3a–e obtained following Method A or B were
isolated, then dissolved in CH2Cl2 (0.05 M), cooled to 0 8C, treated with BF3$Et2O (4 equiv) in one portion, stirred for 15 min and then quenched with satd aq
NaHCO3.
b Diastereomeric ratio of pyrroloisoquinolines 4a–f was determined by HPLC analysis.
c Isolated yield of optically pure product, based on the imide 1.
We were pleased to see that the main products 4a(S) and
4b(S) can be isolated in a high overall yield as optically pure
compounds after a single crystallization from ethanol
(entries 1 and 2, procedure C). Also, the cyclohexyl
derivative 4d(R), after hydrolysis of the acetate groups
can be isolated via crystallization from acetone as a
dihydroxy derivative 5d(R) (entry 4, procedure B). The
remaining pyrroloisoquinolines 4c and 4e can be isolated by
chromatography as respective derivatives 6c(S), 7c(S) and
6e(R) (entries 3 and 5, procedure B).
remaining compounds can be isolated by chromatography
as their respective 2-silyloxy-derivatives.
4. Experimental
4.1. General
Melting points are uncorrected. Optical rotations were
measured at 23 8C with a JASCO Dip-360 digital
polarimeter. IR spectra were obtained using an FT-IR-
1600 Perkin-Elmer spectrophotometer. 1H NMR spectra
were recorded in CDCl3 (except where indicated otherwise)
using a Bruker AM 500 spectrometer. Chemical shifts are
3. Concluding remarks
quoted in d ppm relative to TMS for 1H and CDCl3 for 13
C
In summary, we have successfully developed a simple,
three-step synthesis of hexahydro-pyrroloisoquinolines with
a quaternary carbon stereocenter at the C-10b carbon atom.
The presented methodology utilizes the addition of a
Grignard reagent to the carbonyl group of imide 1, derived
from L-tartaric acid, followed by acetylation and BF3$Et2O
induced cyclization. The acetylation–cyclization sequence
can be run either stepwise or as a one-pot process, in
selected solvents. The crucial step, an acid-catalysed
NMR. Coupling constants J are reported in Hertz. Mass
spectra were recorded using an AMD 640 or a Mariner mass
spectrometer. Kugelrohr distillation was performed using
Buchi glass oven B585. HPLC analyses were preformed
with a Shimadzu LC-8A chromatograph with Hibarw 250-4
LiChrosobw Si 60 (5 mm). Thin-layer chromatography was
carried out on precoated silica gel (Merck Kieselgel 60 F254
,
0.2 mm layer thickness). Flash column chromatography was
preformed using Merck Kieselgel (230–400 mesh). All
reactions were carried out under an argon atmosphere using
anhydrous solvents. Most reagents were obtained from
commercial suppliers and were used without further
purification, unless noted. THF was distilled from Na and
benzophenone, dichloromethane and toluene were distilled
from CaH2.
carbon–carbon
bond-forming
reaction
via
an
N-acyliminium ion offers high stereoselectivity. The degree
of stereoselectivity was shown to be strongly dependent on
the size of the R1 substituent and, to a lesser degree, on the
reaction conditions, that is, choice of solvent, amount of
Lewis acid, temperature, and even concentration of the
substrate. Based on the observed results, participation of
solvent in the cyclization via N-acyliminium cation is
proposed.
4.1.1. Preparation of (2R,3R)-1-[2-(3,4-dimethoxy-
phenyl)-ethyl]-3,4-trimethylsilanyloxy-pyrrolidine-2,5-
dione (1). To a stirred suspension of (2R,3R) 3,4-dihydroxy-
1-[2-(3,4-dimethoxy-phenyl)-ethyl]-pyrrolidine-2,5-dione5k
(29.5 g, 0.1 mol) in pyridine (50 mL, w0.6 mol) and
CH2Cl2 (300 mL) at 0 8C, trimethylsilyl chloride (33 mL,
0.26 mol) was added dropwise. The reaction mixture was
stirred at 0 8C for 15 min followed by an additional 1 h at rt.
The solution was poured into ice-water mixture
(w500 mL). The organic phase was separated, washed
with cold water (3!w300 mL), saturated sodium bicar-
bonate (200 mL), dried (MgSO4), filtered and evaporated.
Our observation that the values of J1,2 coupling constants
of all 10b(S) epimers 4a–f and 6a–f are large (6.8–
8.3 Hz), and the respective values of compounds 10b(R)
series are small (3.1–0.0 Hz), can be used as a rule for
the easy determination of the configuration at C-10b of
pyrroloisoquinolines of this structure. The obtained
pyrroloisoquinolines 4a(S), 4b(S) and 5d(R) can be
isolated in a high overall yield as optically pure
compounds after a single crystallization, while the

Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
949
The crude product was purified by Kugelrohr distillation
(oven temperature 150–160 8C, 0.1 Torr).
4.2.4. Preparation of (2R,3R)-1-[2-(3,4-dimethoxy-
phenyl)-ethyl]-5-hydroxy-5-phenyl-3,4-bis-trimethyl-
silanyloxy-pyrrolidin-2-one (2a). The crude hydroxy-
lactam 2a was obtained following procedure A from
imide 1 (439 mg, 1 mmol) and filtered through a silica gel
pad using t-butylmethyl ether/hexaneZ1:1 as eluent to give
2a as a 10:1 mixture of epimers.
Yield: 41.3 g, 94%. Viscous oil, solidified on storage at rt,
mp 60–61 8C; [a]D C126.8 (c 1.1, CH2Cl2); IR (CH2Cl2):
1
3055, 2961, 1721 cmK1; H NMR: 0.22 (s, 18H), 2.83 (m,
2H), 3.66 (m, 1H), 3.72 (m, 1H), 3.64 and 3.86 (two s, 6H),
4.33 (s, 2H), 6.75 (m, 3H); 13C NMR: K0.01, 33.03 (t),
39.89 (t), 55.83, 55.89, 76.37, 111.37, 112.07, 120.91,
129.96 (s), 147.88 (s), 148.95 (s), 173.21 (s); MS (EI, HR)
m/z: (MC) calcd for C20H33NO6Si2: 439.1846. Found:
439.1842.
Yield: 388 mg, 75%, white solid, crystallization from
hexane gave analytical pure sample of main epimer.
Colourless crystals, mp 90–92 8C; [a]D C23.0 (c 1.0,
1
CH2Cl2); IR (CH2Cl2): 3499, 2961, 1717 cmK1; H NMR:
K0.11 and 0.26 (two s, 18H), 2.74 (m, 2H), 2.86 (m, 1H),
3.58 (m, 1H), 3.76 and 3.80 (two s, 6H), 4.01 (s, 1H,
exchangeable with D2O), 4.14 (d, 1H, JZ6.7 Hz), 4.31 (d,
1H, JZ6.7 Hz), 6.52 (m, 2H), 6.68 (d, 1H, JZ8.0 Hz),
7.32–7.49 (m, 5H); 13C NMR: K0.23, 0.41, 34.40, 42.79,
55.77, 55.87, 75.50, 82.43, 88.69, 111.18, 111.94, 120.58,
126.77, 128.49, 128.61, 131.75, 139.98, 145.42, 148.79,
172.24; MS (LSIMS, HR) m/z: (MCNaC) calcd for
C26H39NO6NaSi2: 540.2214. Found: 540.2221.
4.2. General procedures for the preparation of hexa-
hydropyrrolo-isoquinolines [4a–f(S),(R)]
4.2.1. Procedure A. To a solution of imide 1 (878 mg,
2 mmol) in dry THF (3 mL), an organomagnesium bromide
(3 mmol) in THF (3 mL) was added dropwise at 0 8C. The
reaction mixture was stirred at 0 8C for 15 min, gradually
warmed up to rt, and stirring was continued until TLC
indicated the disappearance of 1 (approx. 0.5 h). The
reaction mixture was poured into ice-cold semi-satd aq
NaHCO3 (30 mL) and extracted with t-butyl methyl ether
(3!30 mL). The combined extracts were washed with ice-
cold water, dried (MgSO4), filtered and evaporated in vacuo.
The crude hydroxy-lactam 2a–f was dissolved in dry MeCN
(10 mL), and after cooling to 0 8C, dimethylaminopyridine
(270 mg, 2.2 mmol) and Ac2O (756 mL, 8 mmol) were
added. The cooling bath was removed and stirring was
continued at rt for 3 h, then BF3$Et2O (1.14 mL, 8 mmol)
was added in one portion. The mixture was stirred at rt for
10 min then cooled to 0 8C, quenched with satd aq NaHCO3
(5 mL) and extracted with CH2Cl2 (3!20 mL). The
combined extracts were washed with water (2!20 mL),
dried (MgSO4), filtered and evaporated in vacuo. The
product was purified by flash column chromatography on
silica gel to yield pyrroloisoquinolines as a mixture of
epimers. The yields of 4a–f(S),(R) are calculated based on a
sequence of three-steps from 1.
4.2.5. Preparation of (2R,3R)-3,4,5-triacetoxy-1-[2-(3,4-
dimethoxy-phenyl)-ethyl]-5-phenyl-pyrrolidin-2-one
(3a). Crude 3a was obtained from 1 (439 mg, 1 mmol)
according to procedure C and purified by flash column
chromatography on silica gel using ethyl acetate/hexaneZ
1:1 as an eluent.
Yield: 75 mg, 15%; white semisolid; IR (CH2Cl2): 2977,
1755, 1731 cmK1
.
Selected data of the main product taken from the 8:1
mixture of epimers.
1H NMR: 2.06, 2.17 and 2.21 (three s, 9H), 2.68 (m, 2H),
3.05 (m, 1H), 3.42 (m, 1H), 3.79 and 3.81 (two s, 6H), 5.66
(d, 1H, JZ5.9 Hz), 5.56 (d, 1H, JZ5.9 Hz), 6.51 (m, 2H),
6.70 (d, 1H, JZ6.7 Hz), 7.43 (m, 3H), 7.53 (m, 2H); 13C
NMR: 20.41, 20.68, 21.77, 33.25, 43.48, 55.80, 55.90,
74.87, 78.15, 93.34, 111.26, 111.92, 120.49, 125.77, 128.90,
129.36, 131.03, 138.36, 147.67, 149.93, 168.98, 169.43,
169.50, 170.09.
4.2.2. Procedure B. The crude hydroxylactam 2, obtained
according to procedure A was acetylated in acetone (0.2 M/
acetone, DMAP 1.1 equiv, Ac2O, 4.0 equiv, 0 8C/rt, 3 h)
and treated at rt with BF3$Et2O (3 equiv) added in one
portion. Workup and purification of obtained pyrroloiso-
quinolines 4a–f(S),(R) as in procedure A.
4.2.6. Preparation of (1S,2R,10bS and 10bR)-1,2-di-
acetoxy-8,9-dimethoxy-10b-phenyl-1,2,3,5,6,10b-hexa-
hydro-pyrrolo [2,1-a]isoquinolin-3-one [4a(S) and
4a(R)]. Procedure A, yield: 82%, 4a(S): 4a(R)Z3:1,
Procedure B, yield: 83%, 4a(S): 4a(R)Z1.9:1.
4.2.3. Procedure C. The acetylated lactam 3, obtained
according to procedure A or B was isolated as follows: the
reaction mixture was poured into ice-cold water and
extracted twice with CH2Cl2, collected extracts were
washed with cold water, satd aq sodium bicarbonate, and
again with water, dried (MgSO4) and evaporated. Crude 3
was carefully dried at rt under high vacuum (0.1 Torr, 2 h),
then dissolved in CH2Cl2 (0.05 M), cooled to 0 8C and with
vigorous stirring, BF3$Et2O (4 equiv) was added in one
portion. Stirring at 0 8C was continued for 15 min and then
the reaction mixture was quenched by the addition of satd aq
NaHCO3. Workup and purification of the obtained
pyrroloisoquinolines 4a–f(S),(R) was as in procedure A.
Procedure C, The crude reaction mixture of 4a(S): 4a(R)Z
24:1 was crystallized from ethanol to give pure 4a(S). Yield:
69% (three-steps), white solid. The spectroscopic and
physical properties of 4a(S) and 4a(R) were previously
reported.8
4.2.7. Preparation of (1S,2R,10bS and 10bR)-1,2-di-
acetoxy-8,9-dimethoxy-10b-methyl-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinolin-3-one [4b(S) and
4b(R)]. Procedure A, yield: 85%, 4b(S): 4b(R)Z5.6:1.
Procedure B, yield: 83%, 4b(S): 4b(R)Z3.4:1.

950
Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
Procedure C, the isolation procedure of hydroxyamide 2b
was modified: for the extraction of 2b dichloromethane was
used. The crude reaction mixture of 4b(S): 4b(R)Z17.9:1
was crystallized from ethanol to give pure 4b(S). Yield:
73% (three-steps).
Oil; IR (CH2Cl2): 2936, 2857, 1753, 1702 cmK1; MS (ES,
HR) m/z: (MCNaC) calcd for C24H31NO7Na: 468.1993.
Found: 468.2013.
Selected data for the mixture of epimers 4d(S): 4d(R)Z
1:4.5.
Compound 4b(S). Colourless crystals, mp 168–169 8C
(ethanol); [a]D C152 (c 1.2, CH2Cl2); IR (CH2Cl2): 2939,
1752, 1715 cmK1;1HNMR:1.65(s, 3H), 2.14and2.24(twos,
6H), 2.71 (m, 1H), 2.96 (m, 1H), 3.12 (m, 1H), 3.81 and 3.82
(two s, 6H), 4.41 (dd, 1H, JZ13.1, 6.2 Hz), 5.46 (d, 1H, JZ
7.9 Hz), 5.67 (d, 1H, JZ7.9 Hz), 6.26 and 6.58 (two s, 2H);
13C NMR: 20.68, 20.86, 23.44, 27.85 (t), 34.57 (t), 55.86,
55.89, 59.52 (s), 72.34, 79.32, 107.41, 111.73, 124.41 (s),
131.24 (s), 148.26 (s), 148.52 (s), 164.32 (s), 169.70 (s),
170.47(s);MS(ES, HR)m/z: (MCHC) calcd for C19H24NO7:
378.1547. Found: 378.1552. Anal. Calcd for C19H23NO7: C,
60.47; H, 6.14; N, 3.71. Found: C, 60.51; H, 6.08; N, 3.70.
Compound 4d(S). 1H NMR: 2.08 and 2.22 (two s, 6H), 3.79
and 3.85 (two s, 6H), 4.50 (m, 1H), 5.48 (d, 1H, JZ7.9 Hz),
5,76 (d, 1H, JZ7.9 Hz), 6.48 and 6.55 (two s, 2H).
Compound 4d(R). 1H NMR: 1.83 and 2.18 (two s, 6H), 2.66
(dd, 1H, JZ16.1, 3.9 Hz), 2.91 (m, 1H), 3.25 (m, 1H), 3.80
and 3.86 (two s, 6H), 4.44 (ddd, 1H, JZ13.3, 7.0, 1.3 Hz),
5.15 (d, 1H, JZ2.3 Hz), 5,65 (d, 1H, JZ2.3 Hz), 6.54 and
6.58 (two s, 2H); 13C NMR: 20.71, 20.69, 26.15 (s), 26.57
(t), 27.23 (t), 27.60 (t), 28.07 (t), 29.86 (t), 37.67 (t), 49.64,
55.74, 55.93, 69.35 (s), 75.10, 75.92, 109.85, 111.57, 126.11
(s), 126.65 (s), 146.97 (s), 147.94 (s), 167.44 (s), 167.44 (s),
169.67 (s), 169.85 (s).
Compound 4b(R). Selected data taken from the mixture of
epimers 4b(S): 4b(R)Z5.6:1
4.2.10. Preparation of (1S,2R,10bS and 10bR)-1,2-
diacetoxy-10b-isopropyl-8,9-dimethoxy-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinolin-3-one [4e(S) and
4e(R)]. Method A, yield: 80%, 4e(S): 4e(R)Z1:6.3.
1H NMR: 1.68 (s, 3H), 1.69 and 2.20 (two s, 6H), 5.17, 5.55,
6.47, and 6.59 (four s, 4H).
4.2.8. Preparation of (1S,2R,10bS and 10bR)-1,2-di-
acetoxy-8,9-dimethoxy-10b-phenylethynyl-1,2,3,5,6,10b-
hexahydro-pyrrolo [2,1-a]isoquinolin-3-one [4c(S) and
4c(R)]. Procedure A, yield: 81%, 4c(S): 4c(R)Z9.5:1.
Method B, yield: 80%, 4e(S): 4e(R)Z1:11.
Method C, yield: 77%, 4e(S): 4e(R)Z1:2.5.
Oil; IR (CH2Cl2): 2966, 2939, 1753, 1704 cmK1; MS (ES,
HR) m/z: (MCNaC) calcd for C21H27NO7Na: 428.1680.
Found: 428.1704.
Procedure B, yield: 83%, 4c(S): 4c(R)Z9.2:1.
Procedure C, yield: 78%, 4c(S): 4c(R)Z23:1
Selected data for the mixture of epimers 4e(S): 4e(R)Z
1:2.5.
Oil; IR (CH2Cl2): 3008, 2939, 2232, 1754, 1722 cmK1; MS
(EI, HR) m/z: (MC) calcd for C26H25NO7: 463.1631. Found:
463.1646.
1
Compound 4e(S). H NMR: 0.82 (d, 1H, JZ7.3 Hz), 1.19
(d, 1H, JZ7.3 Hz), 2.09 and 2.21 (two s, 6H), 3.78 and 3.85
(two s, 6H), 4.52 (m, 1H), 5.50 (d, 1H, JZ8.0 Hz), 5.73 (d,
1H, JZ8.0 Hz), 6.50 and 6.57 (two s, 2H).
Selected data for the mixture of epimers 4c(S): 4c(R)Z
9.2:1.
Compound 4c(S). 1H NMR: 2.14 and 2.25 (two s, 6H), 2.75
(m, 1H), 2.98, (m, 1H), 3.32 (m, 1H), 3.83 and 3.87 (two s,
6H), 4.40 (ddd, 1H, JZ13.1, 6.2, 1.6 Hz), 5.84 (d, 1H, JZ
7.8 Hz), 5.80 (dd, 1H, JZ7.8, 1.1 Hz), 6.60 (s, 1H), 6.86 (s,
1H), 7.30–7.43 (m, 5H); 13C NMR: 20.66, 20.92, 27.56 (t),
35.48 (t), 55.92 (overlapped signals of two carbons), 58.43
(s), 74.38, 78.82, 85.44 (s), 87.37 (s), 108.14, 111.67, 121.81
(s), 124.77 (s), 127.44 (s), 128.35, 128.97, 131.86, 148.46
(s), 149.10 (s), 167.62 (s), 169.76 (s), 170.20 (s).
1
Compound 4e(R). H NMR: 0.89 (d, 3H, JZ7.0 Hz), 1.09
(d, 3H, JZ7.0 Hz), 1.83 and 2.18 (two s, 6H), 2.68 (m, 1H),
2.92 (m, 1H), 3.25 (m, 1H), 3.80 and 3.87 (two s, 6H), 4.46
(dd, 1H, JZ13.3, 6.3 Hz), 5.17 (d, 1H, JZ2.0 Hz), 5.61 (s,
1H), 6.55 and 6.59 (two s, 2H); 13C NMR: 17.38, 20.02,
20.64, 20.90, 28.12, 37.54, 39.11, 55.69, 55.78, 69.48,
74.92, 75.89, 109.57, 111.46, 126.30, 126.50, 146.92,
147.84, 167.42, 169.61, 169.82.
4.2.11. Preparation of (1S,2R,10bS and 10bR)-1,2-
diacetoxy-8,9-dimethoxy-10b-vinyl-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinolin-3-one [4f(S) and 4f(R)].
Procedure A, yield: 38%; 4f(S): 4f(R)Z4.6:1.
Compound 4c(R). 1H NMR: 1.67 and 2.16 (two s, 6H), 3.85
and 3.88 (two s, 6H), 2.90 (m, 1H), 5.13 (s, 1H), 6.61 (s, 1H).
4.2.9. Preparation of (1S,2R,10bS and 10bR)-1,2-di-
acetoxy-10b-cyclohexyl-8,9-dimethoxy-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinolin-3-one [4d(S) and
4d(R)]. Procedure A, yield: 50%, 4d(S): 4d(R)Z1:10.
Oil; IR (CH2Cl2): 2939, 2855, 1753, 1716 cmK1; MS (ES,
HR) m/z: (MCNaC) calcd for C20H23NO7Na: 412.1367.
Found: 412.1380.
Procedure B, yield: 80%, 4d(S): 4d(R)Z1:19.
Procedure C, yield: 77%, 4d(S): 4d(R)Z1:4.5.
Selected data for the mixture of epimers 4f(S): 4f(R)Z4.6:1.
Compound 4c(S). 1H NMR: 2.12 and 2.19 (two s, 6H), 2.69

Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
951
(m, 1H), 2.95 (m, 1H), 3.08 (m, 1H), 3.80 and 3.86 (two s,
6H), 4.31 (ddd, 1H, JZ12.9, 6.3, 2.5 Hz), 5.04 (d, 1H, JZ
17.1 Hz), 5.36 (d, 1H, JZ10.4 Hz), 5.54 (d, 1H, JZ7.9 Hz),
5.63 (dd, 1H, JZ7.9, 1.1 Hz), 6.09 (dd, 1H, JZ17.1,
10.4 Hz), 6.59 and 6.64 (two s, 2H); 13C NMR: 20.67,
20.86, 24.51 (t), 35.15 (t), 55.79, 55.89, 63.53 (s), 74.08,
79.82, 108.02, 111.74, 117.23 (t), 125.58 (s), 127.88 (s),
136.19 (s), 148.12 (s), 148.71 (s), 168.12 (s), 169.72 (s),
170.38 (s).
followed by the tert-butyldimethylchlorosilane (120 mg,
0.8 mmol). The stirring was continued for 24 h at rt. The
mixture was poured into water, extracted with ethyl acetate
(2!10 mL), washed with water and brine then dried over
MgSO4, and evaporated under reduced pressure. The
residue was purified by flash column chromatography to
give optical pure derivatives 6a–f(S) and 6a–f(R)
4.3.1. Preparation of (1S,2R,10bS and 10bR)-2-(tert-
Butyl-dimethyl-silanyloxy)-1-hydroxy-10b-phenyl-8,9-
dimethoxy-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]iso-
quinolin-3-one [6a(S)] and [6a(R)]. The spectroscopic and
physical properties of 6a(S) and 6a(R) were previously
reported.8
1
Compound 4f(R) epimer. H NMR: 1.70 and 2.14 (two s,
6H), 3.79 and 3.87 (two s, 6H), 4.38 (ddd, 1H, JZ12.8, 6.0,
1.0 Hz), 5.05 (d, 1H, JZ17.0 Hz), 5.15 (s, 1H), 5.29 (d, 1H,
JZ10.4 Hz), 5.62 (s, 1H), 6.06 (dd, 1H, JZ17.0, 10.4 Hz),
6.47 and 6.60 (two s, 2H).
4.3.2. Preparation of (1S,2R,10bS and 10bR)-2-(tert-
butyl-dimethyl-silanyloxy)-1-hydroxy-8,9-dimethoxy-
10b-methyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]iso-
quinolin-3-one [6b(S)] and [6b(R)]. Compound 6b(S).
Yield: 61%; oil; [a]D C195.0 (c 1.1, CH2Cl2); IR (CH2Cl2):
3685, 3610, 2932, 1704 cmK1; 1H NMR: 0.17 and 0.21 (two
s, 6H), 0.92 (s, 9H), 1.52 (s, 3H), 2.57 (br s, 1H,
exchangeable with D2O), 2.64 (m, 1H), 2.88 (m, 1H), 2.99
(m, 1H), 3.84 and 3.85 (two s, 6H), 4.03 (d, 1H, JZ8.3 Hz),
4.30 (ddd, 1H, JZ11.4, 6.1, 1.4 Hz), 4.37 (d, 1H, JZ
8.3 Hz), 6.53 and 6.97 (two s, 2H); 13C NMR: K5.01,
K4.21, 18.34 (s), 21.82, 25.87, 28.03 (t), 33.87 (t), 55.84,
56.02, 59.33 (s), 76.93, 82.50, 108.07, 111.48, 124.17 (s),
133.00 (s), 148.02 (s), 168.22 (s); MS (EI, HR) m/z: (MC)
calcd for C21H33NO5Si: 407.2128. Found: 407.2138.
4.2.12. Preparation of (1S,2R,10bR)-10b-cyclohexyl-1,2-
dihydroxy-8,9-dimethoxy-1,2,3,5,6,10b-hexahydro-pyr-
rolo[2,1-a]isoquinolin-3-one [5d(R)]. The crude mixture of
4d(S),(R) obtained from imide 1 (878 mg, 2 mmol) using
procedure B, was dissolved at rt in dry MeOH (20 mL)
containing MeONa (54 mg, 1 mmol). The solution was
stirred until TLC indicated the disappearance of the
substrate (w0.5 h), then the reaction was quenched by the
addition of a small piece of dry ice and evaporated in vacuo.
The residue was dissolved in CH2Cl2 (w20 mL), the
precipitate was filtered off, washed with CH2Cl2 and the
filtrate was evaporated. The residue was crystallized from
methanol–ethyl acetate mixture to give pure dihydroxy-
pyrroloisoquinoline 5d(R).
Yield: 368 mg, 51%; colourless crystals; mp 236–238 8C;
[a]D K115.3 (c 1.0, CH2Cl2); IR (CH2Cl2): 3565, 3357,
Compound 6b(R). Yield: 11%; white crystals; mp
158–160 8C (t-butylmethylether–hexane); [a]D K126.8 (c
2935, 1685 cmK1
.
1.0, CH2Cl2); IR (CH2Cl2): 3685, 3560, 2934, 1697 cmK1
;
1H NMR: 0.20 and 0.22 (two s, 6H), 0.93 (s, 9H), 1.67 (s,
3H), 2.65 (dd, 1H, JZ15.8, 3.8 Hz), 2.83 (m, 1H), 3.05 (m,
1H), 3.85 and 3.89 (two s, 6H), 4.05 and 4.09 (two s, 2H),
4.32 (dd, 1H, JZ13.2, 5.5 Hz), 6.57 and 6.63 (two s, 2H);
13C NMR: K5.24, K4.67, 18.07 (s), 25.72, 26.71, 28.58 (t),
34.29 (t), 55.89, 56.22, 66.00 (s), 77.83, 78.01, 108.03,
112.46, 127.46 (s), 128.03 (s), 148.50 (s, overlapped signals
of two carbons), 170.07 (s); MS (EI, HR) m/z: (MC) calcd
for C21H33NO5Si: 407.2128. Found: 42.2133.
1H NMR (CDCl3CD2O): 1.12 (m, 4H), 1.25 (m, 1H), 1.45
(m, 1H), 1.65 (m, 1H), 1.78 (m, 3H), 2.02 (m, 1H), 2.64 (dd,
1H, JZ16.4, 5.0 Hz), 2.93 (m, 1H), 3.18 (m,1H), 3.83 and
3.87 (two s, 6H), 4.04 (d, 1H, JZ5.8 Hz), 4.26 (m, 1H), 4.41
(d, 1H, JZ5.8 Hz), 6.55 and 7.27 (two s, 2H); 13C NMR:
26.32 (t), 26.84 (t), 27.00 (t), 27.21 (t), 27.54 (t), 28.64 (t),
36.05 (t), 47.51, 55.71, 56.15, 66.63 (s), 76.11, 76.65,
111.86, 111.98, 126.72 (s), 127.63 (s), 146.48 (s), 147.98
(s), 172.75 (s); MS (ES, HR) m/z: (MC) calcd for
C20H27NO5: 361.1889. Found: 361.1903. Anal. Calcd for
C20H27NO5: C, 66.46; H, 7.53; N, 3.88. Found: C, 66.35; H,
7.38; N, 3.84.
4.3.3. Preparation of (1S,2R,10bS and 10bR)-2-(tert-
butyl-dimethyl-silanyloxy)-1-hydroxy-8,9-dimethoxy-
10b-phenylethynyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
a]isoquinolin-3-one [6c(S) and 6b(R)]. Compound 6c(S).
Yield: 68%; oil; [a]D C129.7 (c 1, CH2Cl2); IR (CH2Cl2):
4.3. General procedure for the preparation of 2-(tert-
butyl-dimethyl-silanyloxy)-hexahydropyrrolo-iso-
quinolines [6a–f(S),(R)]
1
3603, 3544, 2958, 2858, 1713 cmK1; H NMR: 0.21 and
0.24 (two s, 6H), 0.958 (s, 9H), 2.63 (br d, 1H, JZ10.0 Hz,
exchangeable with D2O), 2.74 (ddd, 1H, JZ16.1, 4.4,
1.8 Hz), 2.93 (m, 1H), 3.24 (m, 1H), 3.87 and 3.90 (two s,
6H), 4.05 (m, 1H), 4.34 (ddd, 1H, JZ13.0, 6.3, 1.9 Hz),
4.42 (dd, 1H, JZ8.3, 1.2 Hz), 6.58 (s, 1H), 7.19 (s, 1H),
7.3–7.43 (m, 5H); 13C NMR: K4.97, K4.36, 18.39 (s),
25.73, 27.59 (t), 35.04 (t), 55.90, 56.08, 59.06 (s), 77.38,
82.48, 85.64 (s) 88.33 (s), 108.35, 111.42, 121.45 (s), 124.54
(s), 128.31 (s), 128.42, 129.12, 131.91, 148.38 (s), 148.81
(s), 168.54 (s); MS (ES, HR) m/z: (MCNaC) calcd for
C28H35NO5NaSi: 516.2177. Found: 516.2182.
The mixture of diacetoxy-pyrroloisoquinolines 4a–f(S),(R)
(0.5 mmol) was dissolved at rt in dry MeOH (10 mL)
containing MeONa (16 mg, 0.3 mmol). The solution was
stirred until TLC indicated the disappearance of the
substrate (w0.5 h), then the reaction was quenched by the
addition of a small piece of dry ice and evaporated in vacuo.
The residue was dissolved in CH2Cl2 (w5 mL), the
precipitate was filtered off and the filtrate was evaporated
to yield the crude mixture of dihydroxy-pyrroloisoquino-
lines 5a–f(S),(R). The obtained mixture was dissolved in
DMF (3 mL) and imidazole (102 mg, 1.5 mmol) was added
Compound 6c(R). Yield: 7.4%; oil; [a]D K86.7 (c 1, CH2Cl2);

952
Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
IR (CH2Cl2): 3558, 3054, 2932, 2857, 1705 cmK1; 1H NMR:
0.20 and 0.22 (two s), 0.91 (s, 9H), 2.69 (dd, 1H, JZ5.9,
3.5 Hz), 2.87 (m, 1H), 3.26 (m, 1H), 3.26 (m, 1H), 3.88 and
3.92 (two s, 6H), 4.16 (s, 1H), 4.35 (dd, 1H, JZ13.1, 5.4 Hz),
4.46 (br s, 1H), 6.66 (s, 1H), 6.87 (s, 1H), 7.27–7.35 (m, 5H);
13CNMR:K5.15, K4.60, 18.16(s), 25.71,28.16(t),35.14(t),
55.94, 56.31, 63.00 (s), 77.38, 78.79, 85.66 (s), 89.20 (s),
108.46, 112.35, 122.41 (s), 124.51 (s), 128.05 (s), 128.13,
128.46, 131.67, 148.84 (s), 149.04 (s), 170.44 (s); MS (ES,
HR) m/z: (MCNaC) calcd for C28H35NO5NaSi: 516.2177.
Found: 516.2191.
Compound 6e(R). Yield: 67%; oil; [a]D K77.9 (c 1.3,
1
CH2Cl2); IR (CH2Cl2): 3558, 2960, 2857, 1693 cmK1; H
NMR: 0.18 and 0.19 (two s, 6H), 0.91 (d, 3H, JZ7.0 Hz),
0.93 (s, 9H), 1.05 (d, 3H, JZ6.8 Hz), 1.62 (d, 1H, JZ
3.8 Hz, exchangeable with D2O), 2.33 (m, 1H), 2.65 (dd,
1H, JZ16.0, 5.2 Hz), 2.85 (m, 1H), 3.21 (m, 1H), 3.85 and
3.86 (two s, 6H), 4.02 (d, 1H, JZ2.2 Hz), 4.23 (dd, 1H, JZ
3.8, 2.2 Hz), 6.62 and 6.81 (two s, 2H); 13C NMR: K5.17,
K4.54, 18.14, 18.16 (s), 20.34, 25.74 (t), 27.89 (t), 36.66 (t),
38.66, 55.78, 56.16, 69.96 (s), 77.16, 78.35, 108.70, 112.39,
125.91 (s), 128.35 (s), 147.49 (s), 148.28 (s), 171.35 (s); MS
(ES, HR) m/z: (MCHC) calcd for C23H38NO5Si: 436.2514.
Found: 436.2526.
4.3.4. Preparation of (1S,2R,10bS and 10bR)-2-(tert-
butyl-dimethyl-silanyloxy)-10b-cyclohexyl-1-hydroxy-
8,9-dimethoxy-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
a]isoquinolin-3-one [6d(S) and 6d(R)]. Compound 6d(S).
Yield: 6.5%; oil; [a]D C103 (c 1.4, CH2Cl2); IR (CH2Cl2):
3609, 2932, 2856, 1700 cmK1; 1H NMR: 0.20 and 0.23 (two
s, 6H), 0.94 (s, 9H), 0.9–1.4 (m, 6H), 1.69 (m, 2H), 1.90 (m,
2H), 2.27 (m, 1H), 2.64 (dd, 1H, JZ16.2, 4.0 Hz), 1.88 (m,
1H), 3.18 (m, 1H), 3.87 and 3.91 (two s, 6H), 4.13 (d, 1H,
JZ8.3 Hz), 4.47 (ddd, 1H, JZ13.2, 5.9, 1.2 Hz), 4.62 (d,
1H, JZ8.3 Hz), 6.55 and 6.96 (two s, 2H); 13C NMR:
K4.94, K4.14, 18.38 (s), 25.84, 26.36 (t), 26.58 (t), 27.66
(t, overlapped signals of two carbons), 29.11 (t), 30.627 (t),
36.21 (t), 44.76, 55.81, 56.17, 65.74 (s), 76.829, 84.86,
107.36, 111.36, 124.87 (s), 132.53 (s), 147.82 (s), 148.23
(s), 170.57 (s); MS (ES, HR) m/z: (MCNaC) calcd for
C26H41NO5NaSi: 498.2644. Found: 498.2632.
4.3.6. Preparation of (1S,2R,10bS and 10bR)-2-(tert-
butyl-dimethyl-silanyloxy)-1-hydroxy-8,9-dimethoxy-
10b-vinyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoqui-
nolin-3-one [6f>(S) and 6f(R)]. Compound 6f(S). Yield:
60%; oil; [a]D C107.5 (c 1.1, CH2Cl2); IR (CH2Cl2): 3608,
1
2933, 2858, 1709 cmK1; H NMR (C6D6): 0.17 and 0.22
(two s, 6H), 0.93 (s, 9H), 2.31 (d, 1H, JZ6.8 Hz,
exchangeable with D2O), 2.66 (m, 1H), 2.90 (m, 1H), 3.00
(m, 1H), 3.86 and 3.88 (two s, 6H), 4.12 (dd, 1H, JZ8.3,
6.8 Hz), 4.25 (m, 1H), 4.32 (d, 1H, JZ8.3, 1.1 Hz), 5.07 (d,
1H, JZ17.2 Hz), 5.33 (d, 1H, JZ10.5 Hz), 6.11 (dd, 1H,
JZ17.2, 10.5 Hz), 6.58 and 7.10 (two s, 2H); 13C NMR:
K5.01, K4.24, 18.35 (s), 25.27, 27.69 (t), 34.76 (t), 55.87,
56.09, 63.65 (s), 76.58, 83.33, 108.39, 111.56 (t), 125.17 (s),
129.73 (s), 136.70, 148.06 (s), 148.31 (s), 169.04 (s); MS
(EI, HR) m/z: (MCHC) calcd for C22H34NO5Si: 420.2201.
Found: 420.2216.
Compound 6d(R). Yield: 74%; oil; [a]D K75.2 (c 1.0,
1
CH2Cl2); IR (CH2Cl2): 3557, 2933, 2857, 1692 cmK1; H
Compound 6f(R). Yield: 13%; oil; [a]D K111.0 (c 0.6,
CH2Cl2); IR (CH2Cl2): 3558, 2932, 2858, 1699 cmK1; H
NMR: 0.29 and 0.37 (two s, 6H), 1.05 (s, 9H), 1.80 (br s, 1H,
exchangeable with D2O), 2.09 (dd, 1H, JZ15.8, 3.8 Hz),
2.61 (m, 1H), 2.81 (dt, 1H, JZ12.7, 4.3 Hz), 3.36 and 3.37
(two s, 6H), 4.28 (br s, 1H), 4.35 (dd, 1H, JZ12.7, 5.5 Hz),
4.50 (s, 1H), 4.90 (dd, 1H, JZ17.2, 1.0 Hz), 5.069 (dd, 1H,
JZ10.4, 1.0 Hz), 6.23 (s, 1H), 6.30 (dd, 1H, JZ17.2,
10.4 Hz), 6.49 (s, 1H); 13C NMR: K5.25, K4.67, 18.05 (s),
25.69, 28.28 (t), 34.11 (t), 55.86, 56.18, 70.30 (s), 76.91,
77.97, 109.19, 112.42, 117.44 (t), 123.43 (s), 129.12 (s),
139.37, 148.10 (s), 148.66 (s), 170.36 (s); MS (EI, HR) m/z:
(MCHC) calcd for C22H34NO5Si: 420.2201. Found:
420.2210.
NMR: 0.19 and 0.20 (two s, 6H), 0.93 (s, 9H), 0.8–1.3 (m,
5H), 1.60 (m, 2H), 1.75 (m, 2H), 1.94 (m, 1H), 2.11 (m, 1H),
2.67 (ddd, 1H, JZ16.2, 5.3, 2.0 Hz), 2.84 (m, 1H), 3.25 (m,
1H), 3.87 and 3.88 (two s, 6H), 4.01 (d, 1H, JZ2.0 Hz),
4.26 (dd, 1H, JZ3.5, 2.0 Hz), 4.32 (ddd, 1H, JZ13.3, 7.2,
2.0 Hz), 6.63 and 6.79 (two s, 2H); 13C NMR: K5.17,
K4.52, 18.12 (s), 25.73, 26.29 (t), 26.74 (t), 27.78 (t), 28.30
(t), 30.22 (t), 36.95 (t), 49.26, 55.79, 56.24, 70.17 (s), 77.16,
78.24, 109.70, 112.37, 125.75 (s), 128.39 (s), 147.47 (s),
148.26 (s), 171.42; MS (ES, HR) m/z: (MCHC) calcd for
C26H42NO5Si: 476.2827. Found: 476.2842.
4.3.5. Preparation of (1S,2R,10bS and 10bR)-2-(tert-
butyl-dimethyl-silanyloxy)-1-hydroxy-10b-isopropyl-
8,9-dimethoxy-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]i-
soquinolin-3-one [6e(S) and 6e(R)]. Compound 6e(S).
Yield: 10%; oil; [a]D C167.7 (c 0.7, CH2Cl2); IR (CH2Cl2):
3687, 3605, 2960, 2857, 1701 cmK1; 1H NMR: 0.17 and 0.2
(two s, 6H), 0.78 (d, 1H, JZ7.3 Hz), 0.92 (s, 9H), 1.10 (d,
1H, JZ6.6 Hz), 2.40 (d, 1H, JZ5.3 Hz, exchangeable with
D2O), 2.65 (m, 2H), 2.87 (m, 1H), 3.11 (m, 1H), 3.85 and
3.87 (two s, 6H), 4.11 (dd, 1H, JZ8.3, 5.3 Hz), 4.45 (dd,
1H, JZ13.0, 6.1 Hz), 4.56 (d, 1H, JZ8.3 Hz), 6.54 and 6.94
(two s, 2H).
4.3.7. Preparation of (1R,8bS,11aS)-1-hydroxy-
6,7-dimethoxy-10-phenyl-1,3,4,11a-tetrahydro-11-oxa-
2a-aza-pentaleno[6a,1-a]naphthalen-2-one (7). The epi-
meric mixture of 4c(S),(R) (232 mg, 0.5 mmol), obtained
applying procedure A, was dissolved at rt in dry MeOH
(10 mL) containing MeONa (16 mg, 0.3 mmol). The
solution was stirred until TLC indicated the disappearance
of the substrate (w0.5 h), then the reaction was quenched by
the addition of a small piece of dry ice and evaporated in
vacuo. The residue was dissolved in CH2Cl2 (w5 mL), the
precipitate was filtered off and the filtrate was evaporated to
yield the crude mixture of dihydroxy-pyrroloisoquinolines
5c(S),(R). The obtained mixture was then dissolved in THF
(3 mL) and Pd(OAc)2 (23 mg, 0.1 mmol) was added
followed by triethylamine (28 ml, 0.2 mmol) and stirring
was continued for 2 h at rt. The mixture was poured into
13C NMR: K4.98, K4.19, 18.39 (s), 18.73, 20.72, 25.83,
27.77 (t), 34.40, 36.20 (t), 55.81, 56.06, 65.46 (s), 76.73,
84.60, 107.29, 111.39, 124,70 (s), 132.94 (s), 145.93 (s),
148.25 (s), 170.59 (s); MS (ES, HR) m/z: (MCNaC) calcd
for C23H37NO5NaSi: 458.2333. Found: 458.2339.

Z. Kałuz˙a et al. / Tetrahedron 62 (2006) 943–953
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water and extracted with CH2Cl2 (2!15 mL). Collected
extracts were washed with water, semi-satd aq NaHCO3 and
water again then dried over MgSO4, and evaporated under
reduced pressure. The residue was purified by flash column
chromatography to give 7.
Yield: 155 mg, 82%; oil; [a]D C247.0 (c 0.9, CH2Cl2); IR
1
(CH2Cl2): 3556, 3330, 2985, 2939, 1732, 1699 cmK1; H
NMR: 2.69 (dd, 1H, JZ16.5, 3.6 Hz), 2.99 (m, 1H), 3.15
(m, 1H), 3.77 and 3.86 (two s, 6H), 3.94 (br s, 1H,
exchangeable with D2O), 4.38 (dd, 1H, JZ13.0, 5.2 Hz),
4.64 (br s, 1H), 5.03 (d, 1H, JZ3.9 Hz), 5.70 (s, 1H), 6.56
(s, 1H), 6.64 (s, 1H), 7.39 (m, 3H), 7.66 (m, 2H); 13C NMR:
27.53 (t), 36.74 (t), 55.94, 56.14, 73.06 (s), 77.68, 92.06,
101.56, 108.59, 111.23, 124.80 (s), 125. 84, 128.48, 129.53
(s), 129.70 (overlapped signals of two carbons), 148.63
(s) 148.80 (s), 157.29 (s), 170.97 (s); MS (EI, HR) m/z:
(MC) calcd for C22H21NO5: 379.1420. Found: 379.1429.
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Acknowledgements
The authors wish to thank the State Committee for Scientific
Research (Grant 3T09A 16327) for support of this work.
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