Influence of reaction conditions on products of the Pictet-Spengler condensation

Article abstract of DOI:10.1016/j.tet.2011.01.018

The Pictet-Spengler reaction with N-protected α-amino aldehydes was found to be very sensitive to reaction conditions. The outcome of the reaction can be controlled mainly by choice of solvent. Tetrahydro-β-carbolines were obtained in apolar solvents, whi

Full text of DOI:10.1016/j.tet.2011.01.018

Tetrahedron 67 (2011) 1955e1959
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Influence of reaction conditions on products of the PicteteSpengler condensation
,
a,b
Karolina Pulka a , Aleksandra Misicka
*
a Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
b Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2010
Received in revised form 11 December 2010
Accepted 6 January 2011
Available online 13 January 2011
The PicteteSpengler reaction with N-protected a-amino aldehydes was found to be very sensitive to
reaction conditions. The outcome of the reaction can be controlled mainly by choice of solvent. Tetra-
hydro- -carbolines were obtained in apolar solvents, while in polar media octahydro-bipyrroloindoles
b
were the main compounds. Temperature, amount of acid and reaction time also influenced the final
results of the PS reaction. Depending on conditions, products with opposite configuration of stereogenic
centre, descended from amino aldehydes, were formed as byproducts.
Keywords:
Condensation reaction
PicteteSpengler reaction
Ó 2011 Elsevier Ltd. All rights reserved.
Tetrahydro-b-carbolines
a
-Amino aldehydes
Bipyrroloindoles
1. Introduction
depends on the conditions of PS reaction.10,13 During the PS
reaction, racemisation on the stereogenic centre descended from
amino aldehydes may occur and it could lead to mistaken conclu-
sion about the ratio of cis/trans products.
This induced us to investigate in greater detail the influence of
reaction conditions on the products of the PicteteSpengler con-
densation. To our knowledge, no such detailed studies have yet
been reported in the literature.
The PicteteSpengler (PS) reaction1 is widely applied in the
synthesis of tetrahydroisoquinoline and tetrahydro-b-carboline
skeletons, which are found in many alkaloids.2e4 Such moieties are
also useful in peptide chemistry as constrained analogs of aromatic
amino acids. There are known examples of biological active pep-
tides where the incorporation of a tetrahydroisoquinoline or tet-
rahydro-b-carboline moiety into the peptide chain changes the
physico-chemical properties and the biological activity of the
2. Results and discussion
parent peptide.5,6
In recent years, a-amino aldehydes derived from a-amino acids
During the PS reaction with amino aldehydes two types of
products may be formed: 3,4 and 5,6 (Scheme 1).10,14
We investigated the influence of temperature, solvents, reaction
time, and equivalents of added acid on the ratio of possible products.
havebeenwidelyusedascarbonylcomponentsinthePicteteSpengler
reaction.7e10 If such compounds are condensed with tryptophan, a
mixture of diastereomers is formed.11 Additionally, the tetrahydro-
b
-carbolines obtained have carboxyl and amine groups, which make
N-Cbz protected amino aldehydes derived from
-Phe, -Phe were used as carbonyl components. Our earlier studies
have shown that for -amino aldehydes, compounds 3a and 3b are
formed and compound 3b is the main product; for -amino alde-
L-Leu, D-Leu and
them useful in further transformations and libraries of new analogs
L
D
might be formed.12
L
Our laboratory recently studied the influence of the stereogenic
D
centre of the a
-amino aldehyde on the ratio of cis/trans products.11
hydes only compound 4a is formed.11 We have never observed
compound 4b in the reaction mixture; however, Grieco et al.10 did
describe products of this type. We speculate that racemisation of the
starting aldehydes might be one of the causes for obtaining the trans
diastereomer, because chiral amino aldehydes are well-known to
easily undergo such a transformation.15e17 At the beginning of our
studies, the main goal was to investigate the influence of the PS
reaction conditions on amino aldehydes racemisation. Therefore, we
first attempted to study the susceptibility to racemisation directly,
using optical rotation measurement. Samples were prepared in
We found that an intramolecular hydrogen bond, formed during
the PS reaction, may be responsible for the distribution of products.
In the literature, there are other examples of the PicteteSpengler
reaction with the use of amino aldehydes;10,13 comparison of those
results shows that the ratio of the formed products strongly
* Corresponding author. Tel.: þ48 22 822 0211x233; fax: þ48 22 822 5996;
e-mail address: karola@chem.uw.edu.pl (K. Pulka).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.018

1956
K. Pulka, A. Misicka / Tetrahedron 67 (2011) 1955e1959
COOCH3
R
CHO
*
NH2
N
H
+
NHCbz
1
2
H+
COOCH3
H
COOCH3
H
COOCH3
H
COOCH3
H
NH
NH
NH
NH
N
H
N
H
N
H
N
H
H
H
H
H
H
H
H
H
R
NHCbz
R
NHCbz
CbzHN
R
CbzHN
R
3a
3b
4a
4b
COOCH3
COOCH3
COOCH3
COOCH3
2
1
NH
H
NH
H
NH
H
NH
H
3
3a
10b
5a
N
H
5
N
H
N
H
N
H
R
R
R
R
NCbz
NCbz
NCbz
NCbz
H
H
H
H
5b
5a
6a
6b
Scheme 1. Possible products of the PicteteSpengler reaction.
solvents with acid addition, but it proved to be impossible to cal-
culate the racemisation ratio by measuring optical rotation. In the
presence of acid, amino aldehydes condensed to form dehydrated
aldol products, which were confirmed by MS analysis. The
determination of the racemisation ratio of 2 was instead performed
indirectly, by analyzing the products of the PS reaction.
Regarding the PS reaction, we interpreted all our results on the
basis of a known mechanism (Scheme 2). It was postulated that the
reaction could go through two possible paths: A and B. Kowalski
et al.18 and recently Maresh et al.19 showed that path A does not
lead to ‘normal’ PicteteSpengler products with a six-membered
ring. Spiroindolenine 10 is formed via C-3 attack of the indol ring on
the iminium ion 7. It may react further to form compounds of
type 5 and 6. However, conversion of 10 by alkyl shift into the
six-membered carbocation 9 is energetically unfavorable. The
six-membered products of the PS reaction are formed through path
B. Six-membered carbocation 9 is formed by a direct attack of C-2. It
was also confirmed that the formation of spiroindolenine 10 is
reversible, so iminium cation may react through path B to form the
required products.8,18,19
We performed the PicteteSpengler reaction in two types of
solvents: aprotic (CH2Cl2) and protic (CH3OH) with 5 equiv of TFA.
COOCH
COOCH
R
CHO
+
NH
NH
N
H
NHCbz
N
H
1
2
R
NHCbz
7
Attack for L-amino aldehydes
COOCH
COOCH
R
NH
N
H
HC
N
H
H
H
R
NHCbz
NH
O
A
8
OCH Ph
A
B
B
N
H
COOCH
7-trans
COOCH
NH
R
NH
N
H
N+
H
H
R
NHCbz
CbzHN
A
N
H
COOCH3
B
9
10
H
R
N
H
H
COOCH3
O
NH
OCH Ph
7-cis
COOCH3
NH
NH
H
N
H
N
H
R
NCbz
R
NHCbz
H
3,4
5,6
Scheme 2. The PicteteSpengler reaction mechanism.

K. Pulka, A. Misicka / Tetrahedron 67 (2011) 1955e1959
1957
The reaction mixtures were stirred for the first 5 h at ꢀ30, 0 or rt
and then at rt overnight. The results are given in Table 1. In CH2Cl2
we observed the formation of products 3a,b for -amino aldehydes
and 4a for -amino aldehydes as main products. We also observed
L
D
the products with an opposite configuration at C-10 depending on
the temperature (Fig. 1a). This is caused by racemisation due to the
keto-enol tautomerism of parent aldehyde or iminiumeenamine in
iminium ion 7. At higher temperature, higher amounts of product
4a for
L
- and products 3a,b for D-amino aldehydes were observed.
Experiments at different temperatures were also performed in
CH3OH, with surprising results: the reaction was much slower and
TrpeOMe 1 was still present after 24 h. The main product was
compound 5a for
L- and 6a for D-amino aldehydes (Fig. 1b). The
intramolecular hydrogen bond in cation 7-trans, which, in our
opinion, favors diastereomer trans 3b (and cis 4a)11 was probably
broken by the solvent and the attack of C-3 (path A) on the cation
7-cis occurred on the other, less hindered face of the iminium,
forming spiroindolenine 10 (Scheme 2). It did not undergo
a reversible reaction to iminium cation 7 because a topographical
relation of reacting groups was suitable for further conversion into
compound 5a. Spiroindolenine 10 did not also convert into cation
9, because such transformation was found to be energetically
unfavorable.18 Cation 7-trans cannot react via spiroindolenine 10 to
compound 5b, because of the unfavorable topographical relation of
the reacting centers. Additionally, in CH3OH some other products
(marked grey in Fig. 1b) were formed, which were not analyzed in
detail but were shown by LC-MS analysis to be formed from
dehydrated aldol.
Fig. 1. HPLC of reaction mixtures with Cbz-L-Phe-H, in the presence of 5 equiv TFA (a)
in CH2Cl2; (b) in CH3OH; (c) with DMSO addition (d) at different time intervals.
The hydrogen bond in cation 7 is broken and there is a possi-
bility to form higher amounts of compound 3a and spiroindolenine
10 and, further, compound 5. DMSO, as a polar co-solvent, has also
a strong influence on racemisation of the aldehydes stereogenic
centre.
The next experiment was based on kinetic studies of reaction of
Cbz-L-Phe-H in CH2Cl2 (Fig. 1d, Table 3). The reaction was per-
Table 1
Ratio of the PicteteSpengler reaction products determined by HPLC
Aldehyde 2
T [ꢁC]
Solvent
TFA [equiv]
3a,b[%] (3a/3b)a,b
4a [%]a
5a/6a [%]c
Cbz-
L
-Phe-Hd
ꢀ30
0
rt
reflux
rt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
CH3OH
CH3OH
CH3OH
5
5
5
5
1
5
5
5
1
97.7 (14/86)
94.3 (26/74)
90.8 (27/73)
92.0 (30/70)
26.4
18.7
13.8
15.8
19.1
2.3
5.7
9.2
8.0
21.8
6.8
3.7
3.8
10.5
0
0
0
0
36.1/15.7
68.6/5.8
74.8/7.7
72.2/8.2
50.0/20.4
ꢀ30
0
rt
rt
Cbz-
L-Leu-H
ꢀ30
0
rt
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
CH3OH
CH3OH
5
5
5
5
5
5
97.9 (20/80)
97.4 (26/74)
94.1 (27/73)
13.0
17.0
11.8
2.1
2.6
5.9
4.6
4.7
5.8
0
0
0
82.4
78.3
82.4
ꢀ30
0
rt
a
Ratio of 3a/3b obtained in CH2Cl2 was determined by 1H NMR, in the case of reaction with
D
-amino aldehydes only product cis was observed.
b
c
It was not possible to determine the ratio of 3a/3b for reactions performed in CH3OH, due to overlap with signals of 5a and 6a in 1H NMR spectrum.
In the case of reaction with
L
and
D-Leu it was not possible to determined the ratio of 5a/6a.
d
Data for Cbz-
D
-Phe-H and Cbz- -Leu-H are given as the Supplementary data.
D
We also performed the reaction in CH2Cl2 with a smaller
formed at rt with 5 equiv TFA. We analyzed a mixture of products
after 30 min, 1 h, 2 h, 3 h, 5 h and 24 h. After 30 min the ratio of
products 3a,b to 5a was almost 1:1 and small amounts of products
4a and 6a were also observed.
amount of acid (1 equiv) and the results were completely different
from those with 5 equiv (Table 1). The ratio of compounds 3a,b to
4a was almost 1:1 and, additionally, compounds 5a and 6a were
formed. This means that the reaction proceeded by both paths
A and B (Scheme 2). The higher percent of epimeric products in the
reaction performed with 1 equiv of acid in comparison to 5 equiv
(21.8 versus 9.2%) indicates that to maintain stereogenic integrity of
products excess of acid should be used.
To verify the importance of the intramolecular hydrogen bond in
the formation of the PicteteSpengler reaction products, we per-
formed this reaction with different amounts of DMSO (as a hydro-
gen bond breaker) added to CH2Cl2 (Fig. 1c, Table 2).
Table 2
Experiment with different amounts of DMSO (related to TrpeOMe) added to CH2Cl2
(model reaction with Cbz-
termined by HPLC
L
-Phe-H, ꢀ30 ꢁC, 5 equiv TFA). Ratio of products de-
DMSO (equiv)
3a,b [%](3a/3b)a
4a [%]
5a [%]
6a [%]
1
5
98.9 (17/83)
46.8 (26/74)
25.6 (40/60)
25.5 (43/57)
1.1
9.8
14.6
18.6
0
0
33.0
39.0
31.7
10.4
20.8
24.2
20
Excess
The results indicate that the hydrogen bond is responsible for
the formation of compounds 3b and 4a.
a
Ratio of 3a/3b was determined by 1H NMR.

1958
K. Pulka, A. Misicka / Tetrahedron 67 (2011) 1955e1959
Table 3
selectivity of this reaction. Aprotic solvents favor the formation of
six-membered products (tetrahydro- -carbolines), whereas protic
and polar solvents (or co-solvents) favor five-membered products
(octahydro-bipyrolloindoles).
Kinetic experiment in CH2Cl2 at rt (model reaction with Cbz-
Ratio of products determined by HPLC
L-Phe-H, 5 equiv TFA).
b
Time intervals
3a,b [%]
4a [%]
5a [%]
6a [%]
30 min
1 h
2 h
3 h
5 h
43.1
50.6
60.3
68.7
80.0
90.8
5.1
5.7
6.2
6.3
6.6
9.2
49.8
41.9
32.0
23.7
12.4
0
2.0
1.8
1.5
1.3
1.0
0
Our results have shown that the PicteteSpengler reaction with
-amino aldehydes opens up a broad spectrum of synthetic possi-
bilities. We can control the outcome of the reaction depending on
the solvent used.
a
24 h
4. Experimental section
4.1. General procedure
In time, we observed decreasing amounts of products 5a,6a and
increasing amounts of products with the six-membered ring. This
confirmed that the formation of product 5a,6a is reversible and the
direct attack of C-2 of the indole moiety, forming the six-membered
ring, is the driving force of the PicteteSpengler reaction in aprotic
solvents. The rate of formation of spiroindolenine 10 and six-
membered carbocation 9 is probably similar, but the reaction
equilibrium is shifted into products 3,4 because they are thermo-
dynamically favored and do not easily undergo reversible conver-
sion into iminium cation 7.
To prove the reversibility of formation of compounds 5a and 6a,
we attempted to convert products 5a or 6a formed in CH3OH into
3,4 (Fig. 2). Acid and aprotic solvent were necessary for this con-
version. Products 5a or 6a dissolved in CH2Cl2 without acid, or in
CH3OH with acid addition, were stable. However, when the mixture
RP-HPLC was performed using an RP C-12 column (Jupiter 4u
Proteo 90A, ID¼0.46 cm, L¼25 cm). ‘Gradient 1’ for analogs of Cbz-
L
-Phe-H: t¼0 min, 80% A, 20% B, t¼20 min, 3% A, 97% B; the mobile
phases (water, acetonitrile) contained 0.05% TFA. For analogs of
Cbz-
L
-Leu an isocratic program was used ‘gradient 20 t¼0e15 min,
55% A, 45% B, the mobile phase (water, acetonitrile) contained
0.05% HCOOH. For both programs the flow rate was 1 mL minꢀ1 and
l
¼210 nm. All 1H and 2D NMR spectra were acquired using
a 700 MHz spectrometer. For ROESY measurements the standard
pulse sequence was applied with ms mixing time. Mass spectra
were recorded on an LCT TOF spectrometer using electrospray
ionization (positive ion mode) or LC-MS.
obtained in the reaction with L-amino aldehydes in CH3OH, was
4.2. General procedure for PicteteSpengler reaction
redissolved at rt in CH2Cl2 and 5 equiv of TFA was added, we
observed both compounds 3a and 3b in a ratio similar to that
obtained in CH2Cl2 at the same temperature (Table 1). This
confirmed that the formation of spiroindolenine 10 has to be
reversible, otherwise only compound cis 3a should be observed.
All reactions were performed as previously reported11 with
the exception of solvents and temperature.
a-Amino aldehyde
(0.36 mmol) dissolved in 2 mL CH2Cl2 (or CH3OH) was added to
0.33 mmol of TrpeOCH3 in 2 mL CH2Cl2 (or CH3OH). 5 equiv
(0.127 mL) of TFA in 1 mL CH2Cl2 (or CH3OH) was added in three
portions. The reaction mixtures were stirred for 5 h at ꢀ30 ꢁC, 0 ꢁC,
rt, or reflux and then at rt overnight. Then the mixture was
diluted with CH2Cl2 and saturated solution of NaHCO3 was used to
neutralize TFA. For reactions performed in CH3OH, the solvent
was evaporated and the mixture was redissolved in CH2Cl2 and
neutralized with satd NaHCO3. Organic phases were extracted with
satd NaHCO3, washed with brine and dried over MgSO4. For ex-
periments with DMSO addition, the co-solvent was added imme-
diately after the mixing of aldehyde with tryptophan.
The reaction mixtures were analyzed by HPLC. In four cases the
reaction mixtures prepared in CH3OH were purified by semi-pre-
parative HPLC (t¼0 min, 97% A, 3% B, t¼40 min, 3% A, 97% B; the
mobile phases (water, acetonitrile) contained 0.05% TFA) to obtain
20e30 mg of standards for compounds of type 5a and 6a.
Compounds 3a,b and 4a have been isolated and fully charac-
terized before.11
Fig. 2. a) Conversion of 5a (four rings system) into 3,4 (three rings system); (b) 1H
NMR spectrum of the mixture after conversion.
4.2.1. 5-Benzyl 2-methyl (2S,3aR,4S,5aS,10bR)-4-benzyl-1,2,3,3a,4,5,
5a,6-octahydropyrrolo[30,20:3,4]pyrrolo[2,3-b]indole-2,5-dicarboxylate
(5aPhe). Yellow solid, tR (gradient 1)¼14.76 min. Duplicated signals
in NMR resulted from cis/trans isomerisation of amide (ure-
thaneeCbz) bond. 1H NMR (700 MHz, CDCl3) dH 7.44e6.61 (14H, m,
Ar), 5.43 and 5.37 (1H, s, H-5a), 5.24 (q, J 12.3 Hz, CH2Cbz) and 5.13
(2H, q, J 12.2 Hz, CH2Cbz), 4.26 (dd, J 11.6, 4.5 Hz, H-4) and 4.18
(1H,dd, J 10.9, 4.9 Hz, H-4), 4.00e3.96 (1H, 2ꢂdd, J 9.8, 9.3, 5.1,
4.9 Hz, H-2), 3.71 and 3.66 (3H s, OCH3), 3.65 and 3.64 (1H, s, H-3a),
2.59e2.53 (1H, 2ꢂdd, J 14.0, 5.1, 4.9, H-1), 2.48e2.41 (1H, 2ꢂdd, J
14.0, 9.4, 9.3 Hz, H-1),1.96 (1H, dd, J 13.3,11.0 Hz, H-40) and 1.87 (dd,
J 12.7, 12.1 Hz, H-40); 13C NMR (125 MHz, CDCl3) dC 174.0 and 173.9,
155.2 and 154.3, 149.0 and 148.6, 138.1e109.4, 83.1 and 82.4, 72.3
and 71.2, 67.2 and 67.2, 66.7 and 66.3, 63.6 and 62.4, 60.4 and 60.3,
52.4 and 52.3, 42.6 and 42.5, 39.7 and 38.7. COSY (700 MHz, CDCl3)
H-1 (H-1, H-2), H-2 (2ꢂH-1), H-4 (2ꢂH-40). HSQC (700 MHz, CDCl3)
Compounds 3a,b and 4a were stable under conditions men-
tioned above. They did not undergo any conversion in CH2Cl2 or
CH3OH with acid addition, which was confirmed by 1H NMR.
3. Conclusion
In conclusion, our studies have shown that differently struc-
tured products may be obtained depending on PS reaction condi-
tions. We have also confirmed, in greater detail, the well-known
fact that
tions and easily undergo racemisation. Better stereochemistry
control of the PS reaction with -amino aldehydes is obtained at
a-amino aldehydes are very sensitive to reaction condi-
a
lower temperature. The excess of acid used is also crucial, because
in the equimolar condition it is not possible to obtain the desired

K. Pulka, A. Misicka / Tetrahedron 67 (2011) 1955e1959
1959
Ar (129e109), H-5a (83.0 and 82.2), H-3a (72.2 and 71.1), CH2Cbz
(67.10), H-4 (66.6 and 66.2), H-2 (60.3), OCH3 (52.2), H-1 (42.5), H-
40 (39.6 and 38.6). ROESY (700 MHz, CDCl3) H-1 (H-2, H-5a), H-2 (H-
1), H-4 (H-40), H-40(H-4), H-5a (H-1). LC-MS (ESIþ) m/z 484
[MþH]þ, 506 [MþNa]þ. Exact mass calcd for C29H29N3O4Na
[MþNa]þ: 506.2056, found: 506.2079.
(urethaneeCbz) bond. 1H NMR (700 MHz, CDCl3) dH 7.40e6.57 (9H,
m, Ar), 5.68 and 5.60 (1H, s, H-5a), 5.28 and 5.24 and 5.10 and 5.00
(2H, d, J 12.1 Hz, CH2Cbz), 4.71 (br t, J 8 Hz, H-2), 4.61 (br t, J 7 Hz, H-
4) and 4.53 (1H, dd, J 9.9 Hz, 4.9 Hz, H-4), 4.50 (1H, dd, J 11.2, 7.7 Hz,
H-2), 4.28 and 4.24 (1H, s, H-3a), 3.80 and 3.74 (3H, s, OCH3), 2.87
(dd, J 14.0, 8.0 Hz, H-1) and 2.73e2.67 (2H, m, H-1) and 2.58 (dd, J
14.2, 8.7 Hz, H-1), 1.43e1.39 and 1.52e1.46 (1H, m, H-50), 1.30e1.21
(1H, m, H-40), 0.92e0. 81 (1H, m, H-40), 0.79 (d, J 6.3 Hz, H-60) and
0.70 (d, J 6.3 Hz, H-60) and 0.64 (3H, d, J 6.5 Hz, H-60) and 0.57 (3H, d,
J 6.5 Hz, H-60); 13C NMR (125 MHz, CDCl3) dC 169.3 and 168.7, 154.8
and 154.1, 148.9 and 148.6, 137.6e109.8, 82.3 and 81.8, 72.0 and
71.3, 68.0 and 67.4, 64.1 and 63.5, 60.9 and 60.7, 59.3 and 59.2, 53.7
and 53.6, 43.4 and 42.5, 40.7 and 40.2, 25.2 and 23.2, 21.7 and 21.3.
COSY (700 MHz, CDCl3) H-1 (H-2), H-2 (H-1), H-4 (H-40), H-40 (H-4,
H-50), H-50(H-40, H-60), H-60 (H-50). HSQC (700 MHz, CDCl3) Ar
(109.5e130), H-5a (81.47 and 81.9), H-3a (71.0 and 71.6), CH2Cbz
(67.6), H-4 (60.5), H-2 (59.0), OCH3 (53.3), H-40 (43.1 and 42.2), H-1
(40.4 and 39.8), H-50 (24.9), H-60 (22.8 and 21.4). ROESY (700 MHz,
CDCl3) H-1 (H-2, H-5a), H-2 (H-1. H-5a), H-3a (H-40, H-50), H-4 (H-
40, H-60), H-40(H-3a, H-4,), H-50(3a, H-60), H-60(H-40, H-50), H-5a (H-
1, H-2). LC-MS (ESIþ) m/z¼450 [MþH]þ, 472 [MþNa]þ. Exact mass
calcd for C26H32N3O4 [MþH]þ: 450.2393, found: 450.2400.
4.2.2. 5-Benzyl 2-methyl (2S,3aS,4R,5aR,10bS)-4-benzyl-1,2,3,3a,4,
5,5a,6-octahydropyrrolo[30,20:3,4]pyrrolo[2,3-b]indole-2,5-dicarbox-
ylate (6a Phe). Yellow solid, tR (gradient 1)¼15.00 min. Duplicated,
broad signals in NMR resulted from cis/trans isomerisation of amide
(urethaneeCbz) bond. 1H NMR (700 MHz, CDCl3) dH 7.40e6.64
(14H, m, Ar), 5.69 and 5.63 (1H, s, H-5a), 5.26 and 5.10e4.99 (2H, m,
CH2Cbz), 4.77e4.72 (m, H-2 and H-4), 4.68 (1H, dd, J 9.7, 5.8 Hz, H-
4), 4.53 (1H, dd, J 10.3, 6.7 Hz, H-2), 4.22 and 4.20 (1H, s, H-3a), 3.73
and 3.65 (3H, s, OCH3), 2.96 (br d, J 12.1 Hz, H-40), 2.89 (dd, J 13.3,
7.1 Hz, H-1), 2.80e2.75 (1H, m, H-1 and H-40), 2.56 (1H, dd, J 13.3,
11.6 Hz, H-1) and 2.49 (dd, J 13.9, 8.4 Hz, H-1). 2.12 (1H, dd, J 12.9,
9.9 Hz, H-40) and 1.99 (br t, J 11.9 Hz, H-40); 13C NMR (125 MHz,
CDCl3) dC 169.0 and 168.2, 154.9 and 154.7, 148.8 and 148.4,
137.3e109.9, 81.7 and 81.4, 70.1 and 69.3, 67.8 and 67.2, 63.4 and
63.3, 60.0, 59.0 and 58.9, 53.5 and 53.4, 40.3 and 40.0, 39.6 and 38.6.
COSY (700 MHz, CDCl3), H-1 (H-1, H-2), H-2 (2ꢂH-1), H-4 (2ꢂH-40).
HSQC (700 MHz, CDCl3) Ar (110e130), H-5a (81.3 and 81.7), H-3a
(69.2 and 70.1), CH2Cbz (67.6), H-4 (63.4), H-2 (58.7), OCH3 (53.4),
H-1 (40.0 and 40.3), H-40 (38.6 and 39.6). ROESY (CDCl3, 700 MHz)
H-1 (H-2, H-5a), H-2 (H-1, H-5a), H-3a (H-40), H-4 (H-40), H-40(H-3a,
H-4), H-5a (H-1, H-2). LC-MS (ESIþ) m/z 484 [MþH]þ, 506 [MþNa]þ.
Exact mass calcd for C29H30N3O4 [MþH]þ: 484.2236, found:
484.2213.
Acknowledgements
This work was supported by University of Warsaw grant BW
179215 and BW 183205. We thank M. Misiak and W. Kozminski for
2D NMR spectra.
Supplementary data
4.2.3. 5-Isobuthyl 2-methyl (2S,3aR,4S,5aS,10bR)-4-benzyl-1,2,3,3a,4,
5,5a,6-octahydropyrrolo[30,20:3,4]pyrrolo[2,3-b]indole-2,5-dicarbox-
ylate (5a Leu). White solid, tR (gradient 2)¼6.11 min. Duplicated,
broad signals in NMR resulted from cis/trans isomerisation of amide
(urethaneeCbz) bond. 1H NMR (700 MHz, CDCl3) dH 7.39e6.57 (9H,
m, Ar), 5.45 and 5.43 (1H, s, H-5a), 5.23 and 5.16 and 5.10 (2H, sþdd,
J 11.9 Hz, CH2Cbz), 4.73e4.69 (1H, m, H-2), 4.61 (dd, J 9.3, 6.0 Hz, H-
4), 4.47 (1H, dd, J 9.4, 5.7 Hz, H-4), 4.21 and 4.18 (1H, s, H-3a), 3.80
and 3.66 (3H, s, OCH3), 2.89 (dd, J 14.3, 9.5 Hz, H-1) and 2.81e2.80
(2H, m, H-1), 1.47e1.43 and 1.40e1.37 (1H, m, H-50), 1.31e1.20 (1H,
m, H-40), 0.89e0.82 (1H, m, H-40), 0.78 (d, J 6.5 Hz, H-60) and 0.71 (d,
J 6.5 Hz, H-60) and 0.69 (3H, d, J 6.5 Hz, H-60) and 0.62 (3H, d, J
6.6 Hz, H-60); 13C NMR (125 MHz, CDCl3) dC 169.5 and 168.9, 154.5
and 153.6, 148.3 and 148.1, 135.6e110.7, 81.7 and 81.3, 72.5 and 71.3,
67.6 and 67.3, 62.9 and 62.7, 61.2 and 60.4, 59.8 and 59.6, 53.7 and
53.6, 42.9 and 42.6, 40.2 and 40.0, 25.2 and 24.9, 22.4 and 21.4.
COSY (700 MHz, CDCl3) H-1 (H-2), H-2 (H-1), H-4 (H-40), H-40 (H-4,
H-50), H-50(H-40, H-60), H-60 (H-50). HSQC (700 MHz, CDCl3) Ar
(109e130), H-5a (81.7 and 81.5), H-3a (72.6 and 71.6), CH2Cbz
(67.6), H-4 (61.3 and 60.5), H-2 (59.7), OCH3 (54.1 and 53.5), H-40
(42.7 and 42.3), H-1 (40.1), H-50 (25.1), H-60 (22.7 and 21.6). ROESY
(700 MHz, CDCl3) H-1 (H-2, H-5a), H-2 (H-1), H-3a (H-40, H-50), H-4
(H-40, H-50), H-40(H-3a, H-4, H-50), H-50(H-60), H-60(H-40, H-50), H-
5a (H-1). LC-MS (ESIþ) m/z 450 [MþH]þ, 472 [MþNa]þ. Exact mass
calcd for C26H32N3O4 [MþH]þ: 450.2393, found: 450.2400.
Data obtained for Cbz-D-Phe-H and Cbz-D-Leu-H are given as
the Supplementary data. Supplementary data related to this article
can be found online at doi:10.1016/j.tet.2011.01.018. These data
include MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
1. Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030e2036.
2. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797e1842.
3. Bailey, P. D.; McLay, N. R. J. Chem. Soc., Perkin Trans. 1 1993, 441e449.
4. Bailey, P. D.; Clingan, P. D.; Mills, T. J.; Price, R. A.; Pritchard, R. G. Chem. Com-
mun. 2003, 2800e2801.
5. Kazmierski, W. M.; Yamamura, H. I.; Hruby, V. J. J. Am. Chem. Soc. 1991, 113,
2275e2283.
6. Lesma, G.; Meschini, E.; Recca, T.; Sacchetti, A.; Silvani, A. Tetrahedron 2007, 63,
5567e5578.
7. Plate, R.; van Hout, R. H. M.; Behm, H.; Ottenheijm, H. C. J. J. Org. Chem. 1987, 52,
555e560.
8. Nakagawa, M.; Liu, J.-J.; Hino, T. J. Am. Chem. Soc. 1989, 111, 2721e2722.
9. Ducrot, P.; Rabhi, C.; Thal, C. Tetrahedron 2000, 56, 2683e2692.
10. Gomez-Monterrey, I. M.; Campiglia, P.; Bertamino, A.; Aquino, C.; Mazzoni, O.;
Diurno, M. V.; Iacovino, R.; Saviano, M.; Sala, M.; Novellino, E.; Grieco, P. Eur. J.
Org. Chem. 2008, 1983e1992.
ꢀ
ꢀ
11. Pulka, K.; Kulis, P.; Tymecka, D.; Frankiewicz, L.; Wilczek, M.; Kozminski, W.;
Misicka, A. Tetrahedron 2008, 64, 1506e1514.
ꢀ
12. Pulka, K.; Feytens, D.; Misicka, A.; Tourwe, D. Mol. Diversity 2010, 14, 97e108.
13. Gomez-Monterrey, I. M.; Campiglia, P.; Bertamino, A.; Mazzoni, O.; Diurno, M.
V.; Novellino, E.; Grieco, P. Tetrahedron 2006, 62, 8083e8086.
14. Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2006, 128, 14772e14773.
15. Ito, A.; Takahashi, R.; Baba, Y. Chem. Pharm. Bull. 1975, 23, 3081e3087.
16. Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236e239.
17. Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149e164.
4.2.4. 5-Isobuthyl 2-methyl (2S,3aS,4R,5aR,10bS)-4-benzyl-1,2,3,3a,4,
5,5a,6-octahydropyrrolo[30,20:3,4]pyrrolo[2,3-b]indole-2,5-dicarbox-
ylate (6a Leu). White solid, tR (gradient 2)¼6.23 min. Duplicated,
broad signals in NMR resulted from cis/trans isomerisation of amide
18. Kowalski, P.; Bojarski, A. J.; Mokrosz, J. L. Tetrahedron 1995, 51, 2737e2742.
19. Maresh, J. J.; Giddings, L.-A.; Friedrich, A.; Loris, E. A.; Panjikar, S.; Trout, B. L.;
€
Stockigt, J.; Peters, B.; O’Connor, S. E. J. Am. Chem. Soc. 2008, 130, 710e723.