Diastereoselective Pictet-Spengler condensation of tryptophan with α-amino aldehydes as chiral carbonyl components

Article abstract of DOI:10.1016/j.tet.2007.11.037

The Pictet-Spengler reaction of Trp with α-amino aldehydes derived from l and d-amino acids was studied in terms of double stereodifferentiation. The results observed for d-amino aldehydes represent 'matched' situation (one diastereoisomer was formed) whe

Full text of DOI:10.1016/j.tet.2007.11.037

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1506e1514
www.elsevier.com/locate/tet
Diastereoselective PicteteSpengler condensation of tryptophan with
a-amino aldehydes as chiral carbonyl components
Karolina Pulka a, Piotr Kulis a, Dagmara Tymecka a, Lukasz Frankiewicz a, Marcin Wilczek a,
Wiktor Kozminski a, Aleksandra Misicka a,b,
*
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
Received 26 April 2007; received in revised form 26 October 2007; accepted 8 November 2007
Available online 17 November 2007
Abstract
The PicteteSpengler reaction of Trp with a-amino aldehydes derived from L and D-amino acids was studied in terms of double stereodiffer-
entiation. The results observed for D-amino aldehydes represent ‘matched’ situation (one diastereoisomer was formed) whereas with L-amino
aldehydes ‘mismatched’ (two diastereoisomers were formed). The conformation of newly formed six-membered ring was analyzed. It was found
that stable conformers were different for cis and trans isomers.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
considerable importance in the structureeactivity studies of
bioactive peptides. One of the most successfully applied ana-
logs of constrained tryptophan is the one in which the a-nitro-
gen has been linked to the aromatic ring through a methylene
unit, resulting in the six-membered ring derivative 1,2,3,4-
tetrahydro-b-carboline-3-carboxylic acid (Tcc). It is prepared
via a PicteteSpengler cyclization from chiral tryptophan ester
and formaldehyde.7,8 Other aldehydes generate a new stereo-
genic center. Moreover, the products of the PicteteSpengler
reaction can be treated as 1,3-disubstituted tetrahydro-b-
carbolines and cis/trans isomers can be obtained. Therefore,
the main challenge of this cyclization is stereoselectivity and
the ratio of isomers. Different conditions, such as temperature,
solvents, and achiral carbonyl substrates, were studied to im-
prove the selectivity of the PicteteSpengler reaction.9e12 It
was found that the major compound was the cis isomer
when reactions were carried at low temperature. It is also
well known that the Nb-benzyl or Nb-diphenylmethyl
substituted tryptophan esters favored trans isomers.13e17 Re-
cently it has been shown that the PicteteSpengler reaction
of tryptophan allyl ester is cis-specific.18 Other synthetic strate-
gies used to influence the results of the PicteteSpengler con-
densation include the use of chiral catalysts,19 chiral
auxiliaries,20,21 or optically active carbonyl compounds.22
Since its discovery, the PicteteSpengler reaction1 has been
extensively studied in the areas of syntheses of different het-
erocycle systems. One of the possible uses of this reaction is
in preparation of restricted analogs of aromatic amino acids
occurring in proteins (Phe, Tyr, Trp, His). These aromatic
amino acids very often play a crucial role in the interaction
of ligand with the corresponding receptor-protein and there-
fore many efforts have been done to obtain their cyclic or con-
strained analogs. Those analogs have been introduced into the
bioactive peptides to obtain local constraints and therefore
provide insight into the structures required for bioactivity.
Conformational restrictions of such residues have been a suc-
cessful strategy to influence the biological activity, potency,
selectivity, metabolic stability, and many other pharmacologi-
cal properties.2e6
Tryptophan is often a significant part of peptide ligands,
which determines their affinity for receptors therefore different
constrained analogs of this amino acid have recently gained
* Corresponding author.
E-mail address: misicka@chem.uw.edu.pl (A. Misicka).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.037

K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
1507
In this paper we present the diastereoselectivity study of the
PicteteSpengler condensation of tryptophan and a-amino al-
dehydes derived from L or D-amino acids as chiral carbonyl
components. In the literature there are some examples of using
a-amino aldehydes in the PicteteSpengler reaction.23e29 We
have been studied the dependence of isomeric products from
the configuration of the aldehyde and hypothesized on the in-
termediate iminium cation structure as the factor responsible
for the stereoselectivity.
The cis and trans products of such condensations can serve
as constrained tryptophan dipeptide mimetics. Such mimetics
can be incorporated into the peptide sequence to reduce the
flexibility of the peptide chain and probe the bioactive confor-
mation. The trans steroisomer of tetrahydro-b-carboline deriva-
tives could serve as b-turn dipeptide mimetic as it was shown
for similar tetrahydroisoquinoline compounds by Grieco28 and
Lesma.30 Such mimetics incorporated into peptide chain could
introduce b-turn motif in the particular part of peptide chain.
Scheme 2. PicteteSpengler cyclization of L-TrpeOMe with a-amino alde-
hydes derived from D-amino acids.
The resulting diastereomeric products (cis/trans) were ea-
sily separable. The ratio before purification and after silica gel
column was comparable. The well separated signals of the
methyl ester protons allowed us to define the ratio of diaste-
reomers by NMR measurements before purification was
undertaken (Fig. 1).
2. Results and discussion
The configuration at C-1 (the C-3 configuration was known,
because L-TrpeOMe or D-TrpeOMe 1 was used as the starting
material) was determined by 2D NMR (ROESY spectra) ana-
lysis33 and compared with Cook’s method of assignment based
on 13C NMR.34
The PicteteSpengler reaction is an intramolecular cycliza-
tion of the intermediate iminium ion of tryptophan. We uti-
lized a conventional PicteteSpengler synthetic protocol.
Methyl esters of L and D-tryptophan were prepared by a stan-
dard procedure, a-amino aldehydes 2aef were prepared in
good or excellent yields via the FehrentzeCastro procedure31
and used immediately without purification to avoid racemiza-
tion.32 For the protection of the a-amino function of the amino
aldehydes, benzyloxycarbonyl group (Cbz) was chosen. The
reaction was performed in CH2Cl2 in the presence of 5 equiv
of TFA. The temperature conditions were controlled, for 5 h
the reaction was stirred at ꢀ30 ꢁC and then stirring was con-
tinued at room temperature overnight.
Two series of tetrahydro-b-carboline analogs were prepared,
with the moiety of L or D a-amino aldehydes (Schemes 1 and 2).
Scheme 1. PicteteSpengler cyclization of L-TrpeOMe with a-amino alde-
hydes derived from L-amino acids.
Figure 1. 200 MHz 1H NMR spectra before purification for analogs of L (a)
and D (b) amino aldehydes.

1508
K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
Table 1
The ratio of cis/trans stereoisomers determined by NMR measurements
The NOE effect observed between the H-1 and H-3 protons
was diagnostic for identification of the cis configuration. For
the trans diastereomers, the exchange of magnetization among
the H-1 and H-3 protons was not observed (Fig. 2).
Tryptophan
a-Amino aldehyde
cis/trans ratio
determined by NMR [%]
L-Trp
L-Trp
L-Trp
L-Trp
L-Trp
L-Trp
L-Trp
L-Trp
L-Trp
L-Trp
L-Trp
D-Trp
D-Trp
CbzeL-AlaeH
CbzeL-ValeH
CbzeL-LeueH
CbzeL-IleeH
CbzeL-PheeH
CbzeL-NleeH
CbzeD-AlaeH
CbzeD-ValeH
CbzeD-LeueH
CbzeD-allo-IleeH
CbzeD-PheeH
CbzeL-LeueH
CbzeD-LeueH
3-cis a/3-trans a
3-cis b/3-trans b
3-cis c/3-trans c
3-cis d/3-trans d
3-cis e/3-trans e
3-cis f/3-trans f
35/65
0/100
27/73
0/100
29/71
25/75
Our results (Table 1) showed that the PicteteSpengler reac-
tion of L-TrpeOMe with L-amino aldehydes preferentially led
to trans isomers (3aef). In the case of D-amino aldehydes we
expected that the ratio of products would be switched. But re-
actions selectively led to the cis isomers (4aee). No trans
products were observed. Our results from the PicteteSpengler
condensation were opposite to the ones obtained by
Grieco and co-workers.29 They showed that the reaction of
FmoceL-AlaeH with L-DOPA carried at room temperature
leads to the cis isomer as the main product. To prove our
results we performed the epimerization studies and refluxed
small samples of 3-cis, 3-trans, and 4-cis in MeOH in the pres-
ence of TFA. The ratio of cis/trans isomers was not changed
after 3 h of reflux.
The PicteteSpengler cyclization was also performed with
the D-TrpeOMe and both CbzeL-LeueH and CbzeD-LeueH
(2c). From the reaction with L-amino aldehyde only one iso-
mer was obtained and this was designated as the cis isomer.
In the case of D-amino aldehydes, the trans isomer was instead
favored (the cis compound was the minor product).
4-cis a
4-cis b
100/0
100/0
100/0
100/0
100/0
100/0
15/85
4-cis c
4-cis d
4-cis e
5-cis c
6-cis c/6-trans c
In general, when both substrates for PicteteSpengler
cyclization have the same configuration (L,L or D,D) the diaste-
reomeric mixture of cis and trans 1,3-disubstituted 1,2,3,4-tet-
rahydro-b-carbolines is formed (‘mismatched’ situation) and
the major compound is the trans diastereomer (65e100%).
In the case when the configuration of the stereogenic centers
in the substrates is in opposition to each other (L,D or D,L)
the PeS cyclization gave only cis diastereomer (‘matched’
situation).
We hypothesized that the FelkineAhn model and hydrogen
bonded intermediate can explain the observed results (Fig. 3a
and b). This is in agreement with earlier model of Thal pre-
sented for tryptamine.25,27
In the reaction with L-amino aldehydes nucleophilic attack
occurs preferentially from the face opposite to the ester group.
A hydrogen bond is formed between iminium and benzyloxy-
carbonyl groups and stabilizes such pseudocyclic structure, ex-
plaining the predomination of the trans diastereomer. On the
Figure 2. 500 MHz ROESY spectra for 3-cis e (a) and 3-trans e (b).
Figure 3. (a) For L-amino aldehydes and (b) for D-amino aldehydes.

K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
1509
Table 2
Experimental and calculated values of 3J for cis and trans isomers
other hand for the cis isomer the nucleophilic attack occurs
from the same face as the ester group and there is a slight un-
favorable steric interaction between R and the iminium nitro-
gen. The smaller the R, the higher the amount of cis isomer
that is observed, this explains the highest amount of cis com-
pound with CbzeL-AlaeH. For b-branched amino aldehydes
the steric hindrance results in unfavorable interactions and in
those cases the cis isomer is not formed.
3J (H-3, H-4) for cis
diastereomer [Hz]
3J (H-3, H-4) for trans
diastereomer [Hz]
Experimental
values
Calculated values
Experimental
values
Calculated values
A
B
C
D
11.50
4.00
4.71
1.65
11.81
3.88
6.0
2.0
5.49
1.34
11.74
4.28
For D-amino aldehydes, attack from the ester group face is
preferred. Because the hydrogen bond stabilizes the intermedi-
ate structure, only the cis compound is formed. This is be-
cause, in the intermediate leading to the trans diastereomer
there would be unfavorable interactions, and the transition
state would be less stable and in effect trans isomer is not
formed.
Cook and co-workers16,34 found that of the two possible
half chair conformations for cis isomer, conformer B should
represent the more stable form (Fig. 4). Both substituents
are located in the equatorial position and are devoid of the un-
favorable 1,3-interactions. This is in agreement with our inter-
pretation. For the trans isomer they established that conformer
D is more stable, this is opposite to our observations.
We suppose that for our compounds, the more stable con-
former is C. The values of the coupling constant (3J ) between
H-3 and H-4 protons were compared with typical values of
vicinal H, H coupling constant in cyclohexane (HaeHa 3J
8e13 Hz, HaeHe 3J 2e6 Hz, HeeHe 3J 1e4 Hz) and with
values calculated for 3-cis c and 3-trans c by PCModel35
(Table 2). This proves that the chemical environment for
H-3 proton is different in cis and trans diastereomers.
These observations were confirmed by ROESY spectra
(Fig. 5). For cis compounds the NOE effect was observed be-
tween the H-3 proton and only one H-4a proton. The COOCH3
group was located in the equatorial position. Such an observa-
tion is possible only in the B conformer. On the other hand the
NOE effect for the trans isomer was observed between H-3
and both H-4a and H-4b protons. This means that COOCH3
Figure 5. 500 MHz ROESY spectra illustrating mutual interactions of the H-3
and H-4 protons.
group is located in the axial position. This suggests that the
conformational equilibrium is shifted to the C form for the
trans analog.
3. Conclusion
We studied the dependence of diastereomeric products of
the PicteteSpengler cyclization from the structure and chiral-
ity of substrates. We have found that there is chirality transfer
from C-2 of a-amino aldehyde to the newly created stereo-
genic center in the tetrahydro-b-carboline derivatives. When
the reaction is performed with L-TrpeOMe, L-amino alde-
hydes lead to the mixture of products with the dominance of
the trans isomer (more than 65%), however, the reaction
with D-amino aldehydes is completely selective and leads to
only one diastereomer established as the cis tetrahydro-b-carb-
oline derivative. Condensation of D-TrpeOMe and L-alde-
hydes gives only the cis isomer while the reaction with
Figure 4. Conformational analysis of cis (a) and trans (b) 1,3-disubstituted tetra-
hydro-b-carbolines derived from a-amino aldehydes.

1510
K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
D-aldehydes provides a mixture of cis/trans isomers with domi-
nance of the trans compound.
(15 mL) was added. The reaction mixture was cooled to ꢀ30
to ꢀ40 ꢁC and TFA (1.148 mL, 14.9 mmol) in CH2Cl2 (2 mL)
was added dropwise. The reaction mixture was cooled
(ꢀ30 ꢁC) for 5 h and left overnight at room temperature.
Then the mixture was diluted with 20 mL CH2Cl2 and satu-
rated solution of NaHCO3 (25 mL) was used to neutralize
the residual TFA. It was stirred for 30 min and layers were
separated. The organic phase was extracted with saturated
NaHCO3 (3ꢂ20 mL), washed with brine (2ꢂ20 mL), and
dried over MgSO4. After evaporation yellow foams were
obtained. The ratio of the cis/trans isomers in the crude mix-
ture after the reaction was determined by 1H NMR
(based on the integration of separated peaks of methyl ester
group). Isomers were isolated by flash chromatography
(CHCl3eAcetone).
Futhermore, we have demonstrated that the ester group in
the trans isomer is located in the axial position and more stable
is the conformer when R group (at C-1) is equatorially located.
For the cis isomer the more stable conformer is the one in
which both groups are equatorially located.
Our results are potentially useful for the synthesis of a wide
range of building blocks, peptidomimetic or alkaloid motifs,
which needs defined configuration of substituents. The trans
steroisomer of tetrahydro-b-carboline derivatives incorporated
into peptide chain could introduce b-turn motif in the particu-
lar part of peptide chain. It is also possible to use the obtained
tetrahydro-b-carbolines for further cyclization with the forma-
tion of additional five- or six-membered rings.
4. Experimental
4.2.1. Methyl ester of (1S,3S,10S ) and (1R,3S,10S )-1-[10-
[(N-benzyloxycarbonyl)amino]ethyl]-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid (3-cis a and 3-trans a)
4.1. General
Reagents and solvents were purchased from commercial
suppliers and used as received.
The ratio of cis/trans isomers determined before purifica-
1
tion by H NMR (200 MHz) was 35/65.
RP-HPLC was performed using a RP C-18 column (Dis-
covery BIO Wide Pore C18, ID¼0.46 cm, L¼25 cm,
PS¼5 mm). Gradient t¼0 min, 97% A, 3% B, t¼20 min,
30% A, 70% B was used, flow rate: 1 mL minꢀ1, l¼230 nm.
The mobile phases (water, acetonitrile) contained 0.05%
TFA. TLC analysis was performed on precoated plates of si-
lica gel 60 F254 (Merck). Silica gel 60 (0.063e0.2 mm) from
Merck was used for flash chromatography. All 1H NMR spec-
tra were recorded on a Varian Unity Plus 200 or 500 MHz
spectrometers at 300 K with TMS as the internal standard.
13C NMR spectra were acquired as 2D HSQC (quaternary
and carbonyl carbons were not observed). The 2D COSY
and ROESY spectra were acquired using 500 or 700 MHz
spectrometers. For ROESY measurements the standard pulse
sequence was applied with mixing time of ms. Mass spectra
were recorded on a LCT TOF spectrometer using electrospray
ionization (positive ion mode). Optical rotations were mea-
sured on a PerkineElmer 241 polarimeter. Melting points
were measured on a Stuart Scientific melting point apparatus
and are uncorrected.
a-Amino aldehydes 2aef derived from D or L-amino acids
with Cbz for protection of the amino group were prepared
according to the procedure previously described and used in
the next step without purification.31
L and D-TrpeOMe$HCl was converted into the free base by
the stirring in the mixture of CHCl3 and saturated solution of
NaHCO3 for 30 min. Layers were separated and the organic
one was washed with brine and dried over MgSO4. After eva-
poration a yellowish solid was obtained.
cis 3a: Yield: 21%; yellowish foam, mp 76e79 ꢁC; [a]D20
ꢀ62.6 (c 1, CHCl3); tR¼16.26 min; Rf (CHCl3eAcetone 8:2)
0.50; IR (KBr): cmꢀ1 3335, 3059, 3033, 2951, 1697, 1511,
1453, 1337, 1267, 1238, 1059, 741, 697; 1H NMR
(500 MHz, CDCl3): d 1.05 (d, J¼6.5 Hz, 3H, CH3), 2.79
(mABx
,
J¼13 Hz, J¼3 Hz, 1H, H-4a), 3.12 (dddABx
,
J¼14.5 Hz, J¼2.75 Hz, J¼1.5 Hz, 1H, H-4b), 3.73 (dd,
J¼11.5 Hz, J¼4 Hz, 1H, H-3), 3.81 (s, 3H, OCH3), 4.35 (br
s, 1H, H-10), 4.44 (br s, 1H, H-1), 5.11 and 5.15 (qAB
,
J¼12 Hz, 2H, CH2Ph), 5.41 (d, J¼7 Hz, 1H, NHCbz),
7.09e7.48 (m, 9H, Ar), 8.42 (s, 1H, NHin); 13C NMR
(125 MHz, CDCl3): d 14.5 (CH3), 25.8 (C-4), 49.5 (C-10),
52.2 (OCH3), 55.9 (C-1), 56.0 (C-3), 67.0 (CH2Ph), 111.0e
129.0 (Ar); ROESY (500 MHz, CDCl3) H-1 (H-3, H-20),
H-3 (H-1, H-4a, H-10), H-4a (H-3, H-4b), H-4b (H-4a), H-þ10
(H-3, H-20), H-20 (H-1, H-10); ESI m/z: 408.2 [MþH] ,
430.2 [MþNa]þ; exact mass calcd for C23H25N3O4Na
[MþNa]þ: 430.1743. Found: 430.1740.
trans 3a: Yield: 45%; white foam, mp 65e67 ꢁC; [a]D20
þ86.9 (c 1, CHCl3); tR¼16.31 min; Rf (CHCl3eAcetone 8:2)
0.34; IR (KBr): cmꢀ1 3348, 3059, 3032, 2951, 1705, 1502,
1453, 1341, 1330, 1220, 1057, 742, 698; 1H NMR
(500 MHz, CDCl3): d 1.33 (d, J¼6 Hz, 3H, CH3), 3.09
(dddABx, J¼15 Hz, J¼6.25 Hz, J¼2 Hz, 1H, H-4a), 3.24
(dABx, J¼14.5 Hz, 1H, H-4b), 3.63 (s, 3H, OCH3), 4.04 (dd,
J¼5.75 Hz, J¼2.75 Hz, 1H, H-3), 4.36 (br s, J¼1.5 Hz, 1H,
H-10), 4.53 (br s, 1H, H-1), 4.96 (s, 2H, CH2Ph), 5.39 (d,
J¼9 Hz, 1H, NHCbz), 7.07e7.49 (m, 9H, Ar), 8.40 (s, 1H,
NHin); 13C NMR (125 MHz, CDCl3): d 18.3 (CH3), 23.6
(C-4), 49.3 (C-10), 52.3 (OCH3), 53.5 (C-1), 54.2 (C-3), 66.7
(CH2Ph), 111.4e128.6 (Ar); ROESY (500 MHz, CDCl3)
H-1 (H-20), H-3 (H-4a, H-4b), H-4a (H-3, H-4b), H-4b (H-3,
H-4a), H-10 (H-20), H-20 (H-1, H-10); ESI m/z: 408.2
[MþH]þ, 430.2 [MþNa]þ; exact mass calcd for
C23H25N3O4Na [MþNa]þ: 430.1743. Found: 430.1742.
4.2. Standard procedure for the PicteteSpengler reaction
Cbz-L-amino aldehydes or Cbz-D-amino aldehydes
(3.3 mmol) were dissolved in CH2Cl2 (15 mL) and a solution
of L-TrpeOMe or D-TrpeOMe (0.65 g, 2.98 mmol) in CH2Cl2

K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
1511
4.2.2. Methyl ester of (1S,3S,10S ) and (1R,3S,10S )-1-
[10-[(N-benzyloxycarbonyl)amino]-20-methyl-propyl]-
1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid
(3-cis b and 3-trans b)
The ratio of cis/trans isomers determined before purifica-
1
tion by H NMR (200 MHz) was 0/100.
1.83 (m, 1H, H-2b0), 3.12 (ddABx, J¼15 Hz, J¼5.25 Hz, 1H,
H-4a), 3.29 (dABx, J¼15 Hz, 1H, H-4b), 3.66 (s, 3H, OCH3),
4.05 (d, J¼4 Hz, 1H, H-3), 4.32 (m, 1H, H-10), 4.55 (s, 1H,
H-1), 4.84 and 4.94 (qAB, J¼12.25 Hz, 2H, CH2Ph), 5.29 (d,
J¼9 Hz, 1H, NHCbz), 6.94e7.52 (m, 9H, Ar), 8.30 (s, 1H,
NHin); 13C NMR (125 MHz, CDCl3): d 22.4, 23.2 (CH3),
23.2 (C-4), 24.9 (CH), 41.4 (CH2), 51.1 (C-10), 52.1
(OCH3), 52.6 (C-1), 54.1 (C-3), 66.4 (CH2Ph), 111.3e128.3
(Ar); ROESY (500 MHz, CDCl3) H-1 (H-20), H-3 (H-4a,
H-4b), H-4a (H-3, H-4b), H-4b (H-3, H-4a), H-10 (H-20,
H-30, H-40), H-20 (H-1, H-10, H-40), H-30þ(H-10, H-40), H-þ40
(H-10, H-20, H-30); ESI m/z: 450.3 [MþH] , 472.2 [MþNa] ;
exact mass calcd for C26H31N3O4Na [MþNa]þ: 472.2212.
Found: 472.2226.
trans 3b: Yield: 57%; white foam, mp 69e72 ꢁC; [a]D20 þ91.8
(c 1, CHCl3); tR¼17.54 min; Rf (CHCl3eAcetone 8:2) 0.58; IR
(KBr): cmꢀ1 3351, 3059, 3032, 2960, 1706, 1505, 1454, 1330,
1301, 1220, 741, 698; 1H NMR (500 MHz, CDCl3): d 1.08 (d,
J¼7 Hz, 3H, CH3), 1.18 (d, J¼6.5 Hz, 3H, CH3), 1.82e1.89
(m, 1H, H-20), 3.09 (ddABx, J¼14.75 Hz, J¼6 Hz, 1H, H-4a),
3.28 (dABx, J¼15.5 Hz, 1H, H-4b), 3.63 (s, 3H, OCH3), 3.84
(td, J¼10 Hz, J¼1.5 Hz, 1H, H-10), 4.00 (d, J¼5 Hz, 1H, H-3),
4.74 (s, 1H, H-1), 4.79 and 4.91 (qAB, J¼13 Hz, 2H, CH2Ph),
5.37 (d, J¼9 Hz, 1H, NHCbz), 6.84e7.49 (m, 9H, Ar), 8.32 (s,
1H, NHin); 13C NMR (125 MHz, CDCl3): d 19.5, 20.2 (CH3),
23.0 (C-4), 30.2 (CH), 49.9 (C-1), 52.1 (OCH3), 54.1 (C-3),
58.7 (C-10), 66.3 (CH2Ph), 111.4e128.3 (Ar); ROESY
(500 MHz, CDCl3) H-1 (H-10, H-30), H-3 (H-4a, H-4b), H-4a
(H-3, H-4b), H-4b (H-3, H-4a), H-10 (Hþ-10, H-30), H-20 (H-30),
H-30 (H-10, H-20); ESI m/z: 436.2 [MþH] , 458.2 [MþNa]þ; ex-
act mass calcd for C25H29N3O4Na [MþNa]þ: 458.2056. Found:
458.2056.
4.2.4. Methyl ester of (1R,3S,10S,20S )-1-[10-[(N-benzyloxy-
carbonyl)amino]-20-methyl-butyl]-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid (3-trans d)
The ratio of cis/trans isomers determined before purifica-
1
tion by H NMR (200 MHz) was 0/100.
trans 3d: Yield: 68%; yellowish solid, mp 138e141 ꢁC;
[a]2D0 þ112.8 (c 1, CHCl3); tR¼18.49 min; Rf (CHCl3eAce-
tone 8:2) 0.68; IR (KBr): cmꢀ1 3401, 3355, 3060, 3034,
2967, 2948, 1730, 1716, 1497, 1456, 1295, 1224, 1204,
1040, 734, 695; 1H NMR (500 MHz, CDCl3): d 0.96 (t,
J¼7.25 Hz, 3H, CH3 a), 1.15 (d, J¼7 Hz, 3H, CH3 b),
4.2.3. Methyl ester of (1S,3S,10S ) and (1R,3S,10S )-1-[10-
[(N-benzyloxycarbonyl)amino]-30-methyl-butyl]-1,2,3,4-
tetrahydro-b-carboline-3-carboxylic acid (3-cis c
and 3-trans c)
The ratio of cis/trans isomers determined before purifica-
1
tion by H NMR (200 MHz) was 27/73.
1.59e1.73 (m, 3H, H-20 and H-30), 3.09 (dddABx
J¼15.5 Hz, J¼7 Hz, J¼2 Hz, 1H, H-4a), 3.29 (dABx
,
,
J¼15.5 Hz, 1H, H-4b), 3.63 (s, 3H, OCH3), 3.90 (td, J¼
10 Hz, J¼2 Hz, 1H, H-10), 4.00 (d, J¼4.5 Hz, 1H, H-3),
4.73 (s, 1H, H-1), 4.76 and 4.91 (qAB, J¼12.75 Hz, 2H,
CH2Ph), 5.41 (d, J¼10 Hz, 1H, NHCbz), 6.81e7.48 (m, 9H,
Ar), 8.47 (s, 1H, NHin); 13C NMR (125 MHz, CDCl3):
d 11.2, 15.5 (CH3), 22.9 (C-4), 26.1 (CH2), 36.5 (CH), 50.0
(C-1), 52.1 (OCH3), 54.3 (C-3), 57.1 (C-10), 66.2 (CH2Ph),
111.4e128.2 (Ar); ROESY (500 MHz, CDCl3) H-1 (H-10,
H-20, H-50), H-3 (H-4a, H-4b), H-4a (H-3, H-4b), H-4b (H-3,
H-4a), H-10 (H-1, H-20, H-30, H-50), H-20 (H-1, H-10, H-40,
H-50), H-30 (H-10, H-20, H-40), H-40 (H-20, H-50), H-50 (H-1,
H-10, H-20); ESI m/z: 472.2 [MþNa]þ; exact mass calcd for
C26H31N3O4Na [MþNa]þ: 472.2212. Found: 472.2228.
cis 3c: Yield: 13%; white foam, mp 67e69 ꢁC; [a]D20 ꢀ61.5
(c 1, CHCl3); tR¼18.78 min; Rf (CHCl3eAcetone 8:2) 0.62;
1H NMR (500 MHz, CDCl3): d 0.83 (d, J¼6.5 Hz, 3H,
CH3), 0.87 (d, J¼7 Hz, 3H, CH3), 0.99 (pseudo-t,
J¼12.25 Hz, 1H, H-20a), 1.49 (pseudo-td, J¼12.5 Hz,
J¼3.25 Hz, 1H, H-30), 1.64 (m, 1H, H-2b0), 2.78 (mABx, J¼
13 Hz, J¼2.63 Hz, 1H, H-4a), 3.12 (dddABx, J¼14.5 Hz,
J¼4 Hz, J¼2 Hz, 1H, H-4b), 3.70 (dd, J¼10.5 Hz, J¼4 Hz,
1H, H-3), 3.81 (s, 3H, OCH3), 4.28 (br t, J¼10 Hz, 1H,
H-10), 4.46 (br s, 1H, H-1), 5.14 (s, 2H, CH2Ph), 5.17 (d,
J¼8.5 Hz, 1H, NHCbz), 7.10e7.49 (m, 9H, Ar), 8.36 (s, 1H,
NHin); 13C NMR (125 MHz, CDCl3): d 21.5, 23.7 (CH3),
24.7 (CH), 25.7 (C-4), 37.7 (CH2), 52.2 (C-10), 52.3
(OCH3), 56.2 (C-3), 56.8 (C-1), 67.2 (CH2Ph), 111.2e128.6
(Ar); ROESY (500 MHz, CDCl3) H-1 (H-3, H-20, H-40), H-3
(H-1, H-4a, H-10), H-4a (H-3, H-4b), H-4b (H-4a), H-10
(H-3, H-20, H-40), H-20 (H-1, H-10, H-30, H-40), H-30 (H-10,
H-20, H-40), H-40 (H-1, H-10, H-20, H-30); ESI m/z: 472.2
[MþNa]þ; exact mass calcd for C26H31N3O4Na [MþNa]þ:
472.2212. Found: 472.2219.
4.2.5. Methyl ester of (1S,3S,10S ) and (1R,3S,10S )-1-
[10-[(N-benzyloxycarbonyl)amino]phenylethyl]-1,2,3,4-
tetrahydro-b-carboline-3-carboxylic acid (3-cis e
and 3-trans e)
The ratio of cis/trans isomers determined before purifica-
1
tion by H NMR (200 MHz) was 25/75.
cis 3e: yield: 12%; white foam, mp 83e85 ꢁC; [a]D20 ꢀ9.4
(c 0.52, CHCl3); tR¼19.00 min; Rf (CHCl3eAcetone 8:2)
0.61; IR (KBr): cmꢀ1 3335, 3060, 3030, 2951, 2847, 1703,
1511, 1453, 1437, 1343, 1267, 1218, 1041, 742, 698; 1H
NMR (500 MHz, CDCl3): d 2.67e2.85 (mABx and mAB, 3H,
trans 3c: Yield: 41%; white solid, mp 152e153 ꢁC; [a]D20
þ81.4 (c 1, CHCl3); tR¼19.14 min; Rf (CHCl3eAcetone 8:2)
0.47; IR (KBr): cmꢀ1 3412, 3060, 3034, 2957, 2865, 1723,
1495, 1454, 1224, 1213, 1051, 738, 694; 1H NMR
(500 MHz, CDCl3): d 1.03 (d, J¼6 Hz, 3H, CH3), 1.07 (d,
J¼6 Hz, 3H, CH3), 1.47 (m, 1H, H-20a), 1.61 (m, 1H, H-30),
H-4a and H-20), 3.14 (dddABx
,
J¼15 Hz, J¼3.75 Hz,
J¼1.75 Hz, 1H, H-4b), 3.72 (dd, J¼11 Hz, J¼4 Hz, 1H,
H-3), 3.82 (s, 3H, OCH3), 4.52 (br s, 1H, H-10), 4.59 (s, 1H,
H-1), 5.03 (s, 2H, CH2Ph), 5.24 (d, J¼7 Hz, 1H, NHCbz),

1512
K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
7.08e7.5 (m, 14H, Ar), 8.54 (s, 1H, NHin); 13C NMR
(125 MHz, CDCl3): d 25.7 (C-4), 34.8 (C-20), 52.2 (OCH3),
55.7 (C-10), 55.8 (C-1), 56.1 (C-3), 67.0 (CH2Ph), 111.2e
129.0 (Ar); ROESY (500 MHz, CDCl3) H-1 (H-3, H-20),
H-3 (H-1, H-4a, H-10), H-4a (H-3, H-4b), H-4b (H-4þa), H-10
(H-3, H-20), H-20 (H-1, H-10); ESI m/z: 506.2 [MþNa] ; exact
mass calcd for C29H29N3O4Na [MþNa]þ: 506.2056. Found:
506.2052.
J¼10 Hz, 1H, NHCbz), 6.94e7.49 (m, 9H, Ar), 8.35 (s, 1H,
NHin); 13C NMR (125 MHz, CDCl3): d 14.1 (CH3), 22.7,
28.5, 32.2 (CH2), 23.2 (C-4), 52.0 (C-1), 52.1 (OCH3), 53.1
(C-1), 54.2 (C-3), 66.4 (CH2Ph), 111.3e128.3 (Ar); ROESY
(500 MHz, CDCl3) H-1 (H-CH2), H-3 (H-4a, H-4b), H-4a
(H-3, H-4b), H-4b (H-3, H-4a), H-10 (H-CH2); ESI m/z:
450.3 [MþH]þ, 472.2 [MþNa]þ; exact mass calcd for
C26H31N3O4Na [MþNa]þ: 472.2212. Found: 472.2228.
trans 3e: Yield: 40%; white foam, mp 71e72 ꢁC; [a]D20
þ16.7 (c 1, CHCl3); tR¼19.20 min; Rf (CHCl3eAcetone 8:2)
0.45; IR (KBr): cmꢀ1 3350, 3061, 3029, 2950, 2854, 1704,
1497, 1454, 1221, 1048, 1027, 742, 699; 1H NMR (500 MHz,
CDCl3): d 2.89e3.00 (mAB, 2H, H-20), 3.08 (dddABx, J¼
15 Hz, J¼5.75 Hz, J¼1.13 Hz, 1H, H-4a), 3.23 (br dABx, J¼
15.5 Hz, 1H, H-4b), 3.59 (s, 3H, OCH3), 4.02 (br, 1H, H-3),
4.2.7. Methyl ester of (1S,3S,10R)-1-[[(N-benzyloxy-
carbonyl)amino]ethyl]-1,2,3,4-tetrahydro-b-carboline-
3-carboxylic acid (4-cis a)
1H NMR (200 MHz) before purification indicated only one
product (determined as cis isomer).
Yield: 81%; yellowish foam, mp 68e71 ꢁC; [a]D20 ꢀ92.5 (c
1, CHCl3); tR¼16.59 min; Rf (CHCl3eAcetone 8:2) 0.5; IR
(KBr): cmꢀ1 3344, 3059, 3033, 2951, 1732, 1704, 1504,
1453, 1268, 1220, 1057, 741, 697; 1H NMR (500 MHz,
CDCl3): d 1.38 (d, J¼6.5 Hz, 3H, CH3), 2.81 (mABx, J¼
13.25 Hz, J¼2.5 Hz, 1H, H-4a), 3.15 (dddABx, J¼14.5 Hz,
J¼4.13 Hz, J¼1.5 Hz, 1H, H-4b), 3.80 (dd, J¼11 Hz, J¼
4 Hz, 1H, H-3), 3.83 (s, 3H, OCH3), 4.32 (s, 1H, H-1), 4.46
(br s, 1H, H-10), 4.91 (s, 2H, CH2Ph), 5.49 (d, J¼8.5 Hz, 1H,
NHCbz), 7.02e7.49 (m, 9H, Ar), 8.59 (s, 1H, NHin); 13C
NMR (125 MHz, CDCl3): d 18.3 (CH3), 25.3 (C-4), 48.4
(C-10), 52.5 (OCH3), 57.4 (C-1), 56.3 (C-3), 66.7 (CH2Ph),
111.6e128.6 (Ar); ROESY (500 MHz, CDCl3) H-1 (H-3,
H-20), H-3 (H-1, H-4a), H-4a (H-3, H-4b), H-4b (H-4a), H-10
(H-20), H-20 (H-1, H-10); ESI m/z: 408.2 [MþH]þ, 430.2
[MþNa]þ, 837.2 [2MþNa]þ; exact mass calcd for
C23H25N3O4Na [MþNa]þ: 430.1743. Found: 430.1743.
4.38 (br s, 1H, H-10), 4.49 (s, 1H, H-1), 4.84 and 4.89 (qAB
,
J¼12 Hz, 2H, CH2Ph), 5.54 (d, J¼9 Hz, 1H, NHCbz), 7.00e
7.47 (m, 9H, Ar), 8.21 (s, 1H, NHin); 13C NMR (125 MHz,
CDCl3): d 23.3 (C-4), 38.6 (C-20), 50.4 (C-1), 52.0 (OCH3),
54.2 (C-3), 55.1 (C-10), 66.5 (CH2Ph), 111.2e129.2 (Ar);
ROESY (500 MHz, CDCl3) H-1 (H-20), H-3 (H-4a, H-4b),
H-4a (H-3, H-4b), H-4b (H-3, H-4a), þH-10 (H-20), H-20 (H-1,
H-10); ESI m/z: 484.2, 506.2 [MþNa] ; exact mass calcd for
C29H29N3O4Na [MþNa]þ: 506.2056. Found: 506.2055.
4.2.6. Methyl ester of (1S,3S,10S ) and (1R,3S,10S )-1-[10-
[(N-benzyloxycarbonyl)amino]pentyl]-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid (3-cis f and 3-trans f)
The ratio of cis/trans isomers determined before purifica-
1
tion by H NMR (200 MHz) was 29/71.
cis 3f: yield: 16%; white foam, mp 62e64 ꢁC; [a]D20 ꢀ45.0
(c 1, CHCl3); tR¼18.73 min; Rf (CHCl3eAcetone 8:2) 0.62;
IR (KBr): cmꢀ1 3329, 3054, 3033, 2956, 2856, 1745, 1700,
4.2.8. Methyl ester of (1S,3S,10R)-1-[10-[(N-benzyloxy-
carbonyl)amino]-20-methyl-propyl]-1,2,3,4-tetrahydro-
b-carboline-3-carboxylic acid (4-cis b)
1H NMR (200 MHz) before purification indicated only one
product (determined as cis isomer).
1
1539, 1454, 1254, 742, 696; H NMR (500 MHz, CDCl3):
d 0.80 (t, J¼7.25 Hz, 3H, H-50), 1.14e1.49 (m, 6H, H-20,
H-30, and H-40), 2.78 (mABx, J¼13.125 Hz, J¼3.25 Hz, J¼
2.5 Hz, 1H, H-4a), 3.11 (dddABx, J¼14.75 Hz, J¼4.25 Hz,
J¼1.75 Hz, 1H, H-4b), 3.71 (dd, J¼11 Hz, J¼4 Hz, 1H,
H-3), 3.81 (s, 3H, OCH3), 4.2 (m, 1H, H-10), 4.45 (s, 1H,
H-1), 5.14 (s, 2H, CH2Ph), 5.25 (d, J¼8.5 Hz, 1H, NHCbz),
7.09e7.49 (m, 9H, Ar), 8.43 (s, 1H, NHin); 13C NMR
(125 MHz, CDCl3): d 14.0 (CH3), 22.5, 28.7 (CH2), 25.8
(C-4), 52.1 (OCH3), 54.3 (C-10), 56.1 (C-3), 56.5 (C-1), 67.0
(CH2Ph), 111.2e128.5 (Ar); ROESY (500 MHz, CDCl3)
H-1 (H-3, H-CH2), H-3 (H-1, H-4a, H-10), H-4a (H-3, H-4b),
H-4b (H-4a), H-10 (H-3, H-CH2), H-CH2 (H-1, H-10), H-40
(H-1, H-10, H-20, H-30); ESI m/z: 450.2 [MþH]þ, 472.2
[MþNa]þ; exact mass calcd for C26H31N3O4Na [MþNa]þ:
472.2212. Found: 472.2220.
Yield: 89%; yellowish solid, mp 156e159 ꢁC; [a]D20 ꢀ86.4
(c 1, CHCl3); tR¼17.67 min; Rf (CHCl3eAcetone 8:2) 0.69;
IR (KBr): cmꢀ1 3420, 3365, 3343, 3029, 2957, 2895, 2848,
1721, 1497, 1454, 1446, 1222, 1215, 1043, 1035, 748, 699;
1H NMR (500 MHz, CDCl3): d 1.09 (d, J¼6 Hz, 3H, CH3),
1.13 (d, J¼6 Hz, 3H, CH3), 1.91e1.97 (m, 1H, H-20), 2.83
(mABx, J¼13.13 Hz, J¼2.5 Hz, 1H, H-4a), 3.14 (dddABx
,
J¼15 Hz, J¼3.88 Hz, J¼1.5 Hz, 1H, H-4b), 3.80 (dd, J¼
11 Hz, J¼4.5 Hz, 1H, H-3), 3.82 (s, 3H, OCH3), 3.89 (td,
J¼10.13 Hz, J¼2.5 Hz, 1H, H-10), 4.55 (d, J¼1.5 Hz, 1H,
H-1), 4.80 and 4.91 (qAB, J¼12.75 Hz, 2H, CH2Ph), 5.44 (d,
J¼10 Hz, 1H, NHCbz), 6.84e7.48 (m, 9H, Ar), 8.47 (s, 1H,
NHin); 13C NMR (125 MHz, CDCl3): d 19.8, 20.2 (CH3),
25.1 (C-4), 29.9 (CH), 52.2 (OCH3), 53.9 (C-1), 56.2 (C-3),
58.1 (C-10), 66.1 (CH2Ph), 111.7e128.3 (Ar); ROESY
(500 MHz, CDCl3) H-1 (H-3, H-10, H-30), H-3 (H-1, H-4a),
H-4a (H-3, H-4b), H-4b (H-4a), H-10 (H-1, H-20, H-30), H-20
(H-30), H-30 (H-1, H-10, H-20); ESI m/z: 458.2 [MþNa]þ; exact
mass calcd for C25H29N3O4Na [MþNa]þ: 458.2056. Found:
458.2058.
trans 3f: Yield: 44%; white foam; [a]2D0 þ81.9 (c 1,
CHCl3); tR¼18.98 min; Rf (CHCl3eAcetone 8:2) 0.48; 1H
NMR (500 MHz, CDCl3): d 0.93 (t, J¼6.75 Hz, 3H, H-50),
1.32e1.64 (m, 6H, H-20, H-30, and H-40), 3.09 (dddABx
J¼15 Hz, J¼6.25 Hz, J¼1.75 Hz, 1H, H-4a), 3.26 (dABx
,
,
J¼15.5 Hz, 1H, H-4b), 3.63 (s, 3H, OCH3), 4.02 (dd, J¼
6 Hz, J¼2.25 Hz, 1H, H-3), 4.17 (m, 1H, H-10), 4.57 (s, 1H,
H-1), 4.85 and 4.91 (qAB, J¼12.25 Hz, 2H, CH2Ph), 5.32 (d,

K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
1513
4.2.9. Methyl ester of (1S,3S,10R)-1-[10-[(N-benzyloxy-
4.2.11. Methyl ester of (1S,3S,10R)-1-[10-[(N-benzyloxy-
carbonyl)amino]phenylethyl]-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid (4-cis e)
1H NMR (200 MHz) before purification indicated only one
product (determined as cis isomer).
carbonyl)amino]-30-methyl-butyl]-1,2,3,4-tetrahydro-
b-carboline-3-carboxylic acid (4-cis c)
1H NMR (200 MHz) before purification indicated only one
product (determined as cis isomer).
Yield: 76%; yellowish solid, mp 63e65 ꢁC; [a]D20 ꢀ67.1
(c 1, CHCl3); tR¼18.82 min; Rf (CHCl3eAcetone 8:2)
0.71; IR (KBr): cmꢀ1 3328, 3060, 3033, 2954, 2868,
1734, 1694, 1538, 1509, 1454, 1437, 1267, 1218, 1051, 740,
Yield: 92%; white solid, mp 98e100 ꢁC; [a]D20 ꢀ30.8 (c 1,
CHCl3); tR¼19.24 min; Rf (CHCl3eAcetone 8:2) 0.69; IR
(KBr): cmꢀ1 3327, 3060, 3030, 2951, 2848, 1730, 1697,
1539, 1497, 1454, 1267, 1224, 1059, 741, 697; 1H NMR
(500 MHz, CDCl3): d 2.83 (mABx, J¼13.25 Hz, J¼3 Hz,
J¼2.5 Hz, 1H, H-4a), 2.94e3.06 (mAB, 2H, H-20), 3.12
(dddABx, J¼15 Hz, J¼3.5 Hz, J¼1 Hz, 1H, H-4b), 3.75 (dd,
J¼11.5 Hz, J¼3.75 Hz, 1H, H-3), 3.84 (s, 3H, OCH3), 4.29
1
697; H NMR (500 MHz, CDCl3): d 0.99 (d, J¼6 Hz, 3H,
CH3), 1.04 (d, J¼6.5 Hz, 3H, CH3), 1.41 (m, 1H, H-20a),
1.68 (m, 1H, H-20b), 1.75 (m, 1H, H-30), 2.82 (mABx
J¼13.125 Hz, J¼2.63 Hz, 1H, H-4a), 3.14 (ddABx
,
,
J¼13 Hz, J¼3.25 Hz, 1H, H-4b), 3.80 (dd, J¼11 Hz, J¼
4.5 Hz, 1H, H-3), 3.82 (s, 3H, OCH3), 4.30 (s, 1H, H-1),
4.37 (br m, 1H, H-10), 4.80 and 4.89 (qAB, J¼12.5 Hz, 2H,
CH2Ph), 5.34 (d, J¼10 Hz, 1H, NHCbz), 6.87e7.47 (m,
9H, Ar), 8.49 (s, 1H, NHin); 13C NMR (125 MHz, CDCl3):
d 22.1, 23.4 (CH3), 25.0 (C-4), 25.1 (CH), 41.3 (CH2), 50.3
(C-10), 52.3 (OCH3), 56.2 (C-3), 57.2 (C-1), 66.4 (CH2Ph),
111.5e128.3 (Ar); ROESY (500 MHz, CDCl3) H-1 (H-3,
H-20, H-30, H-40), H-3 (H-1, H-4a, H-10), H-4a (H-3, H-4b),
H-4b (H-4a), H-10 (H-3, H-20, H-30, H-40), H-20 (H-1, H-10,
H-30, H-40), H-30 (H-1, H-10, H-20þ, H-40), H-40 (H-þ1, H-10,
H-20, H-30); ESI m/z: 450.3 [MþH] , 472.2 [MþNa] ; exact
mass calcd for C26H31N3O4Na [MþNa]þ: 472.2212. Found:
472.2219.
(s, 1H, H-1), 4.53 (br s, 1H, H-10), 4.81 and 4.86 (qAB
,
J¼12.25 Hz, 2H, CH2Ph), 5.59 (d, J¼7 Hz, 1H, NHCbz),
6.93e7.45 (m, 14H, Ar), 8.39 (s, 1H, NHin); 13C NMR
(125 MHz, CDCl3): d 25.0 (C-4), 38.2 (C-20), 52.3 (OCH3),
54.0 (C-10), 54.7 (C-1), 56.1 (C-3), 66.5 (CH2Ph), 111.4e
128.9 (Ar); ROESY (500 MHz, CDCl3) H-1 (H-3, H-20),
H-3 (H-1, H-4a, H-10), H-4a (H-3, H-4b), H-4b (H-4a), H-10
(H-3, H-20), H-20 (H-10); ESI m/z: 506.2 [MþNa]þ; exact
mass calcd for C29H29N3O4Na [MþNa]þ: 506.2056. Found:
506.2055.
4.2.12. Methyl ester of (1S,3R,10S )-1-[10-[(N-benzyloxy-
carbonyl)amino]-30-methyl-butyl]-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid (5-cis c)
1H NMR (200 MHz) before purification indicated only one
product (determined as cis isomer).
4.2.10. Methyl ester of (1S,3S,10R,20S )-1-[10-[(N-benzyloxy-
carbonyl)amino]-20-methyl-butyl]-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid (4-cis d)
1H NMR (200 MHz) before purification indicated only one
product (determined as cis isomer).
Yield: 90%; yellowish solid, mp 63e65 ꢁC; [a]D20 þ66.6 (c
1, CHCl3); tR¼18.51 min; Rf (CHCl3eAcetone 8:2) 0.71; IR
(KBr): cmꢀ1 3324, 3061, 3033, 2955, 2869, 1734, 1695,
1538, 1508, 1454, 1437, 1266, 1218, 1051, 740, 697; 1H
NMR (500 MHz, CDCl3): d 0.10 (d, J¼6.5 Hz, 3H, CH3),
1.04 (d, J¼6.5 Hz, 3H, CH3), 1.40 (m, 1H, H-20a), 1.68 (m,
1H, H-20b), 1.75 (m, 1H, H-30), 2.83 (mABx, J¼12.88 Hz, J¼
2.38 Hz, 1H, H-4a), 3.14 (dddABx, J¼15 Hz, J¼3.75 Hz,
J¼1.25 Hz, 1H, H-4b), 3.80 (dd, J¼11.25 Hz, J¼4.25 Hz,
1H, H-3), 3.83 (s, 3H, OCH3), 4.31 (s, 1H, H-1), 4.38 (br m,
1H, H-10), 4.81 and 4.91 (qAB, J¼12.5 Hz, 2H, CH2Ph), 5.37
(d, J¼10 Hz, 1H, NHCbz), 6.87e7.47 (m, 9H, Ar), 8.55 (s,
1H, NHin); 13C NMR (125 MHz, CDCl3): d 22.2, 23.4
(CH3), 25.0 (C-4), 25.0 (CH), 41.2 (CH2), 50.3 (C-10), 52.3
(OCH3), 56.2 (C-3), 57.3 (C-1), 66.4 (CH2Ph), 111.4e128.2
(Ar); ROESY (500 MHz, CDCl3) H-1 (H-3, H-20), H-3 (H-1,
H-4a), H-4a (H-3, H-4b), H-4b (H-4a), H-10 (H-20, H-30,
H-40), H-20 (H-30, H-40), H-30 (H-20, H-40), H-40 (H-10, H-20);
ESI m/z: 450.3 [MþH]þ, 472.3 [MþNa]þ; exact mass calcd
for C26H31N3O4Na [MþNa]þ: 472.2212. Found: 472.2219.
Yield: 60%; yellowish solid, mp 109e112 ꢁC; [a]D20 ꢀ81.9
(c 1, CHCl3); tR¼18.66 min; Rf (CHCl3eAcetone 8:2) 0.78;
IR (KBr): cmꢀ1 3398, 3312, 3060, 3033, 2965, 2933, 2876,
1741, 1700, 1538, 1501, 1454, 1269, 1219, 1046, 741, 697;
1H NMR (500 MHz, CDCl3): d 1.02 (t, J¼7.5 Hz, 3H, CH3
a), 1.06 (d, J¼6 Hz, 3H, CH3 b), 1.34 (m, 1H, H-20), 1.69
(m, 1H, H-30a), 1.79 (m, 1H, H-30b), 2.83 (mABx, J¼13 Hz,
J¼2.75 Hz, J¼2.25 Hz, 1H, H-4a), 3.13 (ddABx
,
J¼14.5 Hz, J¼3.25 Hz, 1H, H-4b), 3.80 (dd, J¼11.5 Hz, J¼
4.25 Hz, 1H, H-3), 3.82 (s, 3H, OCH3), 3.90 (td,
J¼9.625 Hz, J¼1.83 Hz, 1H, H-10), 4.54 (s, 1H, H-1), 4.80
and 4.91 (qAB
,
J¼12.75 Hz, 2H, CH2Ph), 5.38 (d,
J¼10.5 Hz, 1H, NHCbz), 6.84e7.48 (m, 9H, Ar), 8.31 (s,
1H, NHin); 13C NMR (125 MHz, CDCl3): d 10.8, 15.8
(CH3), 24.9 (C-4), 26.0 (CH2), 35.9 (CH), 52.2 (OCH3),
54.0 (C-1), 56.1 (C-3), 56.3 (C-10), 66.2 (CH2Ph), 111.5e
128.3 (Ar); ROESY (500 MHz, CDCl3) H-1 (H-3, H-20,
H-30, H-40, H-50), H-3 (H-1, H-4a), H-4a (H-3, H-4b), H-4b
(H-4a), H-10 (H-20, H-30, H-40), H-20 (H-1, H-10, H-30, H-40),
H-30 (H-1, H-10, H-20, H-40), H-40 (H-1, H-10, H-20, H-30),
H-50 (H-1, H-20, H-30); ESI m/z: 450.2 [MþH]þ, 472.2
[MþNa]þ; exact mass calcd for C26H31N3O4Na [MþNa]þ:
472.2212. Found: 472.2217.
4.2.13. Methyl ester of (1S,3R,10R) and (1R,3R,10R)-1-[10-
[(N-benzyloxycarbonyl)amino]-30-methyl-butyl]-1,2,3,4-
tetrahydro-b-carboline-3-carboxylic acid (6-cis c
and 6-trans c)
The ratio of cis/trans isomers determined before purifica-
1
tion by H NMR (200 MHz) was 15/85.

1514
K. Pulka et al. / Tetrahedron 64 (2008) 1506e1514
cis 6c: Yield: 6%; white foam, mp 67e69 ꢁC; [a]D20 þ61.8
References and notes
(c 1, CHCl3); tR¼18.56 min; Rf (CHCl3eAcetone 8:2) 0.67;
IR (KBr): cmꢀ1 3388, 3061, 3033, 2954, 2869, 1703, 1513,
1454, 1437, 1268, 1220, 1028, 740, 698; 1H NMR
(500 MHz, CDCl3): d 0.83 (d, J¼6.5 Hz, 3H, CH3), 0.87 (d,
J¼7 Hz, 3H, CH3), 0.97 (pseudo-t, J¼11.5 Hz, 1H, H-20a),
1.49 (pseudo-td, J¼12.875 Hz, J¼3.75 Hz, 1H, H-30), 1.64
(m, 1H, H-2b0), 2.78 (mABx, J¼12.75 Hz, J¼2.875 Hz, 1H,
H-4a), 3.12 (dddABx, J¼14.5 Hz, J¼4 Hz, J¼2 Hz, 1H, H-4b),
3.71 (dd, J¼11 Hz, J¼4 Hz, 1H, H-3), 3.81 (s, 3H, OCH3),
4.29 (br t, J¼10.25 Hz, 1H, H-10), 4.46 (br s, 1H, H-1), 5.14
(s, 2H, CH2Ph), 5.19 (d, J¼9 Hz, 1H, NHCbz), 7.10e7.50
(m, 9H, Ar), 8.42 (s, 1H, NHin); 13C NMR (125 MHz,
CDCl3): d 21.4, 23.6 (CH3), 24.8 (CH), 25.8 (C-4), 37.6
(CH2), 52.1 (C-10), 52.2 (OCH3), 56.1 (C-3), 56.7 (C-1),
67.0 (CH2Ph), 111.2e128.5 (Ar); ROESY (500 MHz,
CDCl3) H-1 (H-3), H-3 (H-1, H-4a, H-10), H-4a (H-3, H-4b),
H-4b (H-4a), H-10 (H-3, H-20, H-40), H-20 (H-10, H-30, H-40),
H-30 (H-10, H-20, H-40), H-40 (H-10, H-20, H-30); ESI m/z:
472.2 [MþNa]þ; exact mass calcd for C26H31N3O4Na
[MþNa]þ: 472.2212. Found: 472.2232.
1. Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030.
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2. Tourwe, D.; Verschueren, K.; Frycia, A.; Davis, P.; Porreca, F.; Hruby,
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trans 6c: Yield: 49%; white solid, mp 149e152 ꢁC; [a]D20
ꢀ80.4 (c 1, CHCl3); tR¼18.96 min; Rf (CHCl3eAcetone 8:2)
0.44; IR (KBr): cmꢀ1 3412, 3388, 3369, 3060, 3034, 2958,
2865, 1724, 1495, 1454, 1224, 1213, 1051, 738, 694; 1H
NMR (500 MHz, CDCl3): d 0.99 (d, J¼7 Hz, 3H, CH3),
1.04 (d, J¼6.5 Hz, 3H, CH3), 1.43 (m, 1H, H-20a), 1.58 (m,
1H, H-30), 1.79 (m, 1H, H-2b0), 3.09 (dddABx, J¼15 Hz,
J¼6.25 Hz, J¼2 Hz, 1H, H-4a), 3.26 (dABx, J¼15.5 Hz, 1H,
H-4b), 3.63 (s, 3H, OCH3), 4.02 (dd, J¼6 Hz, J¼2.25 Hz,
1H, H-3), 4.28 (br s, 1H, H-10), 4.52 (s, 1H, H-1), 4.81 and
4.91 (qAB, J¼12.25 Hz, 2H, CH2Ph), 5.27 (d, J¼9.5 Hz, 1H,
NHCbz), 6.91e7.50 (m, 9H, Ar), 8.31 (s, 1H, NHin); 13C
NMR (125 MHz, CDCl3): d 22.3, 23.1 (CH3), 23.1 (C-4),
24.8 (CH), 41.3 (CH2), 51.0 (C-10), 52.0 (OCH3), 52.5
(C-1), 54.1 (C-3), 66.3 (CH2Ph), 111.3e128.3 (Ar); ROESY
(500 MHz, CDCl3) H-1 (H-20, H-30), H-3 (H-4a, H-4b),
H-4a (H-3, H-4b), H-4b (H-3, H-4a), H-10 (H-20, H-40), H-20
(H-10, H-40), H-30 (H-40), H-40 (H-20, H-30); ESI m/z:
450.3 [MþH]þ, 472.3 [MþNa]þ; exact mass calcd for
C26H31N3O4Na [MþNa]þ: 472.2212. Found: 472.2216.
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26. De la Figura, N.; Alkorta, I.; Garcıa-Lopez, M. T.; Herranz, R.;
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´
~
Gonzalez-Muniz, R. Tetrahedron 1995, 51, 7841.
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Acknowledgements
31. Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676.
This work was supported in part by EU grant LSHC-CT-
2006-037733. The 700 MHz NMR measurements were ac-
complished at the Structural Research Laboratory, Faculty of
Chemistry, University of Warsaw. We would like to thank
´
Prof. D. Tourwe and Dr. R. Sicinski for fruitful and helpful
discussions and suggestions.
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