(R)-1-Phenylethylamine as chiral auxiliary in the diastereoselective synthesis of tetrahydro-β-carboline derivatives

Article abstract of DOI:10.1139/V07-118

Modified sodium borohydrides were used in the reduction of the imine moiety in compounds containing the (R)-1-arylethylamine motif as a chiral auxiliary. Diastereomeric products were formed with moderate to good stereoselectivity and were effectively sepa

Full text of DOI:10.1139/V07-118

1033
(R)-1-Phenylethylamine as chiral auxiliary in the
diastereoselective synthesis of tetrahydro-␤-
carboline derivatives
Aleksandra Siwicka, Krystyna Wojtasiewicz, Andrzej Leniewski, Jan K. Maurin,
Anna Zawadzka, and Zbigniew Czarnocki
Abstract: Modified sodium borohydrides were used in the reduction of the imine moiety in compounds containing the
(R)-1-arylethylamine motif as a chiral auxiliary. Diastereomeric products were formed with moderate to good
stereoselectivity and were effectively separated by column chromatography.
Key words: asymmetric synthesis, indole alkaloids, hydrogen bond.
Résumé : On a utilisé des borohydrures de sodium modifiés pour effectuer la réduction de la portion imine de compo-
sés contenant un motif (R)-aryléthylamine comme auxiliaire chiral. Il y a formation de produits diastéréomères avec
des stéréosélectivités allant de modérées à bonnes et il est possible de les séparer d’une façon efficace par chromato-
graphie sur colonne.
Mots-clés : synthèse asymétrique, alcaloïdes de l’indole, liaison hydrogène.
[Traduit par la Rédaction] Siwicka et al. 1036
Introduction
of α-PEA, even in the industrial scale, was proven possible,
as illustrated by the development and the scale-up of the
endothelin antagonists synthesis (6). The process involves
the preparation of a racemic intermediate followed by an ef-
ficient dynamic resolution with a chiral amine.
Both enantiomers of 1-phenylethylamine (α-methyl-
benzylamine, α-PEA 3) remain as attractive chirality sources
in various asymmetric transformations. Their use as resolv-
ing agents, chiral ligands in catalytic processes, and syn-
thetic chiral auxiliaries in stereodifferentiating reactions of
prochiral substrates have been the subject of in-depth re-
views (1, 2).
More recently, an interesting example of the use of α-PEA
3 in an asymmetric Strecker reaction leading to enantio-
merically enriched 1-amino-cis-3-azabicyclo[4.4.0]decan-
2,4-diones has been reported (3). In this process, which is
called a second-generation asymmetric synthesis, trimethyl-
silyl cyanide was the reagent allowing a stereoselective
cyanide-ion addition to the prochiral precursor derived from
α-PEA and cyclohexanone derivative. In another application,
3 was used as the chiral auxiliary in the preparation of
enantiopure conformationally constrained Gly-(s-cis)-Pro
Turn Mimetic (4). The reaction of the prochiral imine moi-
ety in α-PEA derivatives gave an access to a variety of
chiral, nonracemic aliphatic amines (5). Conveniently, these
processes can be performed as one-pot procedures. The use
In the field of the stereoselective synthesis of pharmaco-
logically relevant compounds, we presented recently the ap-
plication of α-PEA in the preparation of enantiomerically
pure lortalamine analogues (7) and (R)-(–)-mianserin (8)
compounds that are well-known antidepressants. The
Bischler–Napieralski cyclization followed by diastereo-
selective reduction of the imine bond were the key steps in
the enantiodivergent synthesis of both enantiomers of N-
acetylcalycotomine (9) that was carried out in our laboratory
(10). Encouraged by the positive results of using α-PEA in
the stereoselective formation of isoquinoline alkaloids, we
decided to extend this procedure to tetrahydro-β-carboline
analogues.
Results and discussion
The synthetic sequence started with the reaction of
tryptamine 1 with diethyl oxalate followed by the treatment
with (R)-1-phenylethylamine to afford the diamide 5 almost
quantitatively (Scheme 1).
After careful optimization, we found that the subsequent
Bischler–Napieralski cyclization gave best results when per-
formed in refluxing dichloromethane with POCl3.
Since all attempts to isolate and characterize the resulting
imine 7 were unsuccessful because of its instability as a free
base, we decided to subject its hydrochloride salt to a metal
hydride reduction. Thus, upon treatment with sodium
borohydride in EtOH, a pair of diastereomeric amines 9a
and 9b was formed in 62:38 ratio, respectively, based upon
Received 25 April 2007. Accepted 02 September 2007.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 25 October 2007.
A. Siwicka, K. Wojtasiewicz, A. Leniewski, A. Zawadzka,
and Z. Czarnocki.1 Faculty of Chemistry, Warsaw
University, Pasteura 1, 02-093 Warsaw, Poland.
J.K. Maurin. National Institute of Public Health, Che»mska
30/34, 00-750 Warsaw, Poland; Institute of Atomic Energy,
05-400 Otwock-Ðwierk, Poland.
1Corresponding author (email: czarnoz@chem.uw.edu.pl)
Can. J. Chem. 85: 1033–1036 (2007)
doi:10.1139/V07-118
© 2007 NRC Canada

1034
Can. J. Chem. Vol. 85, 2007
Table 1. Diastereomeric output for the reduction of 7 with various borohydrides.
Entry
Reducing reagent
Yield of 9a
Ratio of 9a:9bb
1
2
NaBH4
NaBH(CH3COO)3
81
88
62:38
75:25
3
4
NaBH[(CH3)2CHCOO]3
84
89
66:34
78:22
NaBH[(CH3)3CCOO]3
aIsolated yield (%) of both 9a and 9b.
1
bEstimated from H NMR on the crude reaction mixture.
Scheme 1. Reaction sequence leading to diastereoselective syn-
thesis of tetrahydro-β-carboline derivatives (9a, 9b, 10a, and
10b).
Accordingly, the increase of steric demands in the
nucleophile and (or) the imine molecules might have a posi-
tive effect on the chirality transfer.
Since it is well-known that sodium borohydride, modified
with controlled amounts of simple carboxylic acids, forms
reducing agents of enhanced selectivity (12), we applied
such combined reagents to C=N bond reduction in 7.
Disappointingly, the diastereoselectivity was not improved
significantly when hydrides such as NaBH(AcO)3, NaBH(i-
PrCOO)3, and NaBH(t-BuCOO)3 were applied.
(COOEt)2
O
NH2
HN
74%
N
N
H
OEt
H
O
1
2
H2N
CH3
O
R
HN
Fortunately, the mixture of isomers could be effectively
separated by column chromatography, affording pure and
stable compounds 9a and 9b. The configuration at C-1
stereogenic centre in compound 9a was assigned as (R) by
the chemical transformation of 9a into (1R)-1-(hydroxy-
methyl)-2-acetyl-1,2,3,4-tetrahydro-β-carboline of known
absolute configuration by the method developed earlier in
our laboratory (13). Full details for this procedure will be
published in due course.
Dioxane, reflux
N
H
NH
CH3
O
3
R = phenyl
4 R = 1-naphthyl
5 R = phenyl 95%
6 R = 1-naphthyl 55%
R
POCl3
Hydride
N
CH2Cl2
reduction
N
H
Seeking further improvement in the stereoselectivity, we
decided to apply the same synthetic sequence using (R)-(+)-
1-(1-naphthyl)ethylamine (4), another well-known and effec-
tive chiral inductor (7), as a chiral auxiliary. Thus, com-
pound 8 was prepared in a good yield from tryptamine 1 and
was consecutively subjected to a series of reactions affording
easily separable diastereomers 10a and 10b. The results
were summarized in Tables 1 and 2.
In contrast to previous results, the increase of steric pa-
rameters neither in the reducing agent molecule nor in the
imine-containing target derivative 8 did not give a significant
improvement of the stereochemical outcome. In a search for
a feasible explanation of the previous observations, we in-
vestigated the problem using quantum chemical methods.
Despite considerable efforts, it was impossible to obtain
good quality monocrystals of imine 7, and therefore we per-
formed a molecular modelling to find its optimal geometry.
The procedure consisted of consecutive molecular- mechanic
search through a conformational space and ab initio calcula-
tions used for conformers to optimize their geometries and
to find the corresponding energies (14).2 The two low-
energy conformers 7a and 7b are shown in Fig. 1, where 7a
has the lowest total electron energy. Noticeably, in both con-
formers 7a and 7b, a strong hydrogen bond between the am-
ide carbonyl group and the indole NH define the shape of
the reacting part of the molecule. As a consequence, the
chiral fragment derived from the 1-phenylethylamine was di-
O
NH
CH3
7
R = phenyl 94%
8 R = 1-naphthyl 92%
R
+
NH
HN
NH
N
H
N
H
H
O
H
O
NH
CH3
CH3
9a
R = phenyl
10a R = 1-naphthyl
9b R = phenyl
10b R = 1-naphthyl
R
R
1H NMR spectrum of the crude reaction mixture. The ratio
of 9a and 9b was not affected neither by a prolonged contact
with strongly basic solution of the reducing agent nor by
solvent variations; these observations ruled out the possibil-
ity of an asymmetric transformation caused by a base-
catalyzed epimerization at C-1 atom.
Therefore, it seemed reasonable to assume that both
diastereomers 9a and 9b were formed in unequal amounts
because of the chiral induction during a kinetically governed
hydride approach to the substrate 7. The prochiral imine
moiety can be regarded as a planar structure resembling a
carbonyl group, and the reduction process can be rational-
ized using the Cram or Felkin stereochemical models (11).
2 We used a Spartan′04 for Windows software for both tasks; a conformational search using MMFF94 force field and a Monte Carlo algo-
rithm was performed. Two different low-energy conformers were selected for further ab initio optimization. A restricted Hartree–Fock
method with the standard 6-31G** basis set was then applied. These calculations showed that the conformational energy ∆E between 7a and
7b was 2.383 kcal/mol.
© 2007 NRC Canada

Siwicka et al.
1035
Table 2. Diastereomeric output for the reduction of 8 with various borohydrides.
Entry
Reducing reagent
Yield of 10a
Ratio of 10a:10bb
1
2
3
4
NaBH4
91
86
93
86
66:34
76:24
64:36
83:17
NaBH(CH3COO)3
NaBH[(CH3)2CHCOO]3
NaBH[(CH3)3CCOO]3
aIsolated yield (%) of both 10a and 10b.
1
bEstimated from H NMR on the crude reaction mixture.
Fig. 1. The structure of conformers 7a and 7b.
conclusions can be drawn from this consideration. First, the
model correctly predicts diastereomer 9a as the major prod-
uct of the reduction process. Second, the bulkiest substituent
of the chiral auxiliary (phenyl or naphthyl ring) is located in
the most-remote part of the molecule and is guided in the
opposite direction to the incoming nucleophile. This model
accounts convincingly for both the relatively low level of
diastereodifferentiation during the addition step and for only
a small improvement after the replacement of the phenyl in
compound 7 by the naphthyl moiety in compound 8.
Conclusion
In the presented approach, we demonstrated the possibil-
ity to extend our earlier findings concerning the diastereo-
selective preparation of tetrahydroisoquinoline derivatives
using enantiopure (R)-1-arylethylamines onto β-carboline an-
alogues.
Despite moderate selectivity, the described method might
be an attractive alternative to the existing procedures (16, 17,
18) because of the relatively high chemical yields and facile
chromatographic separation of diastereomers, which then
may be subjected to further transformations leading to the
pure enantiomers of 1-substitued-tetrahydro-β-carboline de-
rivatives. The work in this area is in progress.
Experimental
Fig. 2. Stereochemical model for the reduction of 7a.
(1R)-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-␤-
carboline-1-carboxamide 9a and (1S)-N-[(1R)-1-
phenylethyl]-2,3,4,9-tetrahydro-1H-␤-carboline-1-
(re)
H
H3B
NH
H
R
carboxamide 9b
N
H
N
In a typical experiment (see Table 1, entry 4), a sample of
compound 5 (335 mg, 1 mmol) was refluxed in methylene
chloride (15 mL) with POCl3 (0.5 mL, 5.5 mmol) for 2 h.
After that time, the volatiles were evaporated, and dry
MeOH (10 mL) was slowly introduced. The mixture was
evaporated into dryness, and the procedure was repeated
twice followed by the evaporation with a fresh portion of
xylene (20 mL) to remove traces of methanol. The residue
was then dissolved in dioxane (20 mL), and a freshly pre-
pared modified borohydride solution was introduced at
10 °C. The borohydride was prepared by stirring NaBH4
(180 mg, 4 mmol) with pivaloyl acid (1.11 g, 12 mmol) in
dry THF (10 mL) for 3 h. The resultant solution was stirred
for 1 h at 10 °C and was poured onto 5% aq. NaOH
(50 mL). The mixture was then extracted with methylene
chloride (3 × 20 mL). After drying and evaporation, the resi-
due was subjected to column chromatography on silica gel
H
N
O
O
NH
CH3
HN
9a
7a
H
CH3
rected apart from the imine area (consult also Fig. 2), thus
lowering its ability to the chirality induction. Apparently,
such a disfavored interaction was not present in the
isoquinoline analogue of imine 7, thus allowing us to ob-
serve much better diastereoselectivity (10).
When a Felkin–Evans trajectory (15) for an early transi-
tion state was applied to conformer 7a (Fig. 2), two major
© 2007 NRC Canada

1036
Can. J. Chem. Vol. 85, 2007
2. E. Juaristi, J. Escalante, J.L. Leon-Romo, and A. Reyes. Tetra-
hedron: Asymmetry, 9, 715 (1998).
3. P. Bisel, K.P. Fondekar, F.J. Volk, and A.W. Frahm. Tetrahe-
using ethyl formate as eluent to afford pure diastereomers 9a
and 9b (Rf values are 0.45 and 0.49, respectively).
Selected data for compound 9a: brown foam (194 mg,
23
1
dron, 60, 10541 (2004).
61%). [α]D +55.2 (c 0.5, CHCl3). H NMR δH: 8.85 (1H,
br s, H-9), 7.96 (1H, br d, J = 7 Hz, NHCHCH3), 7.47 (1H,
d, J = 8 Hz, H-8), 7.38 (1H, br t, J = 2 Hz, H-2) 7.31 (1H, d,
J = 8 Hz, H-5), 7.27–7.24 (3H, m, Harom), 7.21–7.18 (2H, m,
4. F.M. Cordero, F. Pisaneschi, K.M. Batista, S. Valenza, F.
Machetti, and A. Brandi. J. Org. Chem. 70, 856 (2005).
5. G.V. Grishina, E.R. Luk’yaenko, and A.A. Borisenko. Russ. J.
Org. Chem. 41, 807 (2005).
6. C.P. Ascroft, S. Challenger, D. Cifford, A.M. Derrick, Y.
Hajikarimian, K. Slucock, T.V. Silk, N.M. Thomson, and J.R.
Williams. Org. Process Res. Dev. 9, 663 (2005).
7. J. Bia»a, Z. Czarnocki, and J.K. Maurin. Tetrahedron: Asym-
metry, 13, 1021 (2002).
8. J. Paw»owska, Z. Czarnocki, K. Wojtasiewicz, and J.K.
Maurin. Tetrahedron: Asymmetry, 14, 3335 (2003).
9. Z. Czarnocki, D.B. MacLean, and W.A. Szarek Can. J. Chem.
64, 2205 (1986).
H
arom), 7.14 (1H, td, J = 7.5 Hz, J = 1 Hz, H-6), 7.07
(1H, m, H-7), 5.09 (1H, qt, J = 7.5 Hz, H-1′), 4.62 (1H, s,
H-1), 3.26 (1H, dt, J = 13 Hz, J = 5 Hz, H-3), 2.97 (1H, m,
H-3), 2.77 (1H, dt, J = 15.5 Hz, J = 5 Hz, H-4), 2.72–2.66
(1H, m, H-4), 1.54 (3H, d, J = 7 Hz, H-2′). 13C NMR δC:
170.6, 143.0, 136.0, 129.6, 128.7, 127.2, 126.8, 125.8,
121.8, 119.2, 118.0, 111.2, 109.2, 54.7, 48.4, 42.0, 22.5,
22.2. ESI-MS m/z (%): 320 (100%, M + H+). HR-MS
(ES(+)): [M + H]+ calcd. for C20H22N3O: 320.1763; found:
320.1776.
10. M. Zió»kowski, Z. Czarnocki, A. Leniewski, and J. K. Maurin.
1
Selected data for compound 9b: (48 mg, 15%). H NMR
Tetrahedron: Asymmetry, 10, 3371 (1999).
δH: 8.92 (1H, br s, H-9), 7.96 (1H, br d, J = 6.5 Hz,
NHCHCH3), 7.57 (1H, d, J = 8 Hz, H-8), 7.48 (1H, br t, J =
9 Hz, H-2), 7.38–7.33 (5H, m, Harom), 7.20 (1H, m, Harom),
7.16 (1H, m, H-6), 7.08 (1H, m, H-7), 5.06 (1H, qt, J =
7.5 Hz, H-1′), 4.56 (1H, s, H-1), 3.25 (1H, m, H-3), 3.05
(1H, m, H-3), 2.79 (1H, m, H-4), 2.71 (1H, m, H-4), 1.45
(3H, d, J = 6.5 Hz, H-2′). 13C NMR δC: 170.5, 143.1, 136.0,
129.8, 128.7, 127.4, 126.8, 126.1, 121.8, 119.2, 118.0,
111.2, 109.1, 57.7, 48.6, 41.9, 22.4, 22.0. HR-MS (ES(+)):
[M + H]+ calcd. for C20H22N3O: 320.1763; found: 320.1769.
11. E.L. Eliel, and S.H. Wilen. Stereochemistry of organic com-
pounds. John Wiley & Sons. New York. 1994.
12. M. Periasamy, and P. Thirumalaikumar. J. Organomet. Chem.
609, 137 (2000).
13. Z. Araïny, Z. Czarnocki, K. Wojtasiewicz, and J.K. Maurin.
Tetrahedron: Asymmetry, 11, 2793 (2000).
14. Spartan′04 [computer program]. Wavefunction Inc., Irvine,
California, USA, 2005.
15. N. Giubellina, W. Aelterman, and N. De Kimpe. Pure Appl.
Chem. 75, 1433 (2003).
16. P. Roszkowski, K. Wojtasiewicz, A. Leniewski, J.K. Maurin,
T. Lis, and Z. Czarnocki. J. Mol. Catal. A: Chem. 232, 143
(2005).
Acknowledgments
17. U. Rinner, T. Hudlicky, H. Gordon, and G.R. Pettit. Angew.
The support from grant PBZ-KBN-126/T09/13 is grate-
fully acknowledged.
Chem., Int. Ed. 43, 5342 (2004).
18. T. Morimoto, N. Suzuki, and K. Achiwa. Heterocycles, 63,
2097 (2004).
References
1. E. Juaristi, J.L. Leon-Romo, A. Reyes, and J. Escalante. Tetra-
hedron: Asymmetry, 10, 2441 (1999).
© 2007 NRC Canada