Keywords Pictet–Spengler reaction - stereoselectivity - diastereoselectivity - stereocontrol
- glycosides - imines - π-stacking interactions
The Pictet–Spengler condensation[
2
] is one of the most widely used methods for preparing 1,2,3,4-tetrahydro-β-carbolines
and tetrahydroisoquinolines. The reaction has been extensively used for the synthesis
of isoquinoline and indole alkaloids[
3
] and has been studied both under acidic conditions,[
4
] including under microwave irradiation,[
5
] and without the aid of an acid or protic solvent.[
6
] The importance of this reaction has led organic chemists to focus on the development
of stereoselective synthetic routes[
7
] that involve either chiral substrates or chiral reagents, including chiral catalysts.
Scheme 1 The Pictet–Spengler reaction used to prepare cis and trans diastereomeric 1,2,3,4-tetrahydro-β-carboline glycosides
Here, we report a new methodology in which complete stereocontrol of the Pictet–Spengler
conditions results in the formation of 100% cis or trans diastereomeric tetrahydro-β-carboline glycosides from either l - or d -tryptophan methyl ester. The tetrahydro-β-carboline glycosides are important as intermediates
in the synthesis of indolo[2,3-a ]quinolizine alkaloids[
8
] and tetrahydro-β-carboline nucleosides,[
9
] which have the ability to bind with DNA or RNA, or as chiral precursors for the
stereoselective synthesis of a range of indole alkaloids. The interesting and distinguishable
cis and trans stereochemistry of the novel compounds were determined on the basis of 13 C NMR spectroscopic analysis, which supports well-documented compression effects.[
10
]
In our endeavor to synthesize important heterocyclic intermediates for the synthesis
of indolo[2,3-a ]quinolizine alkaloids,[
11
] tryptamine (1a ), or l - or d -tryptophan methyl ester (1b and 1c ) was reacted with di(1,2-O -cyclohexylidene-α-d -xylopentodialdofuranose-5-hydrate)-5,5′:3′,5-dianhydride (2a )[
12
] (the dimeric form of 1,2-O -cyclohexylidene-3-hydroxy-α-d -xylofuranose-5-carbaldehyde) in dichloromethane with a catalytic amount of trifluoroacetic
acid (TFA),[
13
] which resulted in the formation of β-carboline glycoside diastereomers 3a and 3b (dr 14:5), 4a and 4b (dr 25:7), or 5a and 5b (dr 7:2), quantitatively. The diastereomeric ratio was calculated on the basis of
their isolated yield. When the same Pictet–Spengler reaction was conducted between
1a and 1,2-O -cyclohexylidene-3-allyloxy-α-d -xylofuranose-5-carbaldehyde (2b ), or between 1c and 1,2-O -cyclohexylidene-3-propyloxy-α-d -xylofuranose-5-carbaldehyde (2c ), the corresponding two diastereomers 6a and 6b (dr 17:7) or 7a and 7b (dr 9:1),[
14
] were obtained in quantitative yield (Scheme [1 ]). Due to the presence of allyl group the diastereomeric 6a shows some improved stereocontrol over 6b .
The interesting stereochemical aspects of the above 1,3-disubstituted β-carboline
glycosides were investigated by Cook and co-workers,[
10
] who analyzed the 13 C NMR spectral data and showed that C-1 and C-3 carbon signals appeared relatively
downfield in all the cis isomers in comparison to the trans isomers. They reported that for the β-carboline derivatives obtained when L-tryptophan
methyl ester reacted with benzaldehyde, the cis isomer exhibited signals for C-1 and C-3 at δ = 58.7 and 56.9 ppm, respectively,
whereas the corresponding signals of the trans isomer appeared at δ = 54.9 and 52.3 ppm. Hence, the hydrogen atoms attached at C-1
and C-3 are on the same face for cis diastereoisomers whereas they are on opposite faces for the trans diastereoisomers. The chemical shifts of C-1 and C-3 carbon atoms of diastereoisomers
4a , 5b and 7b , in our case, appeared at higher shifts in the 13 C NMR spectra, and were thus assigned as cis isomers, whereas those of the other diastereomers 4b , 5a and 7a with lower δ values, were assigned as the trans isomers. The 13 C NMR chemical shift for C-1 and C-3 of all diastereoisomers are shown in Table [1 ]. The spatial connectivity were revealed by NOE effects and NOESY correlations between
1-H and 3-H for the diastereoisomer 4a , which confirmed its cis stereochemistry, whereas for 4b there was no such connectivity found, which indicates its trans stereochemistry.
Unusually, 1,2-O -cyclohexylidene-3-allyloxy-α-d -xylofuranose-5-carbaldehyde derivatives 2b and 2d
[
15
] react with 1b under the same conditions to form only their respective cis diastereomer 8 and 10 (Scheme [2 ]). Alternatively, they can react with 1c to produce their respective trans diastereomers 9 and 11 , exclusively, with more than 98% isolated yield.
Scheme 2 The unusual kinetic approach leading to stereoselectivity in the Pictet–Spengler reaction
In the mechanism of Pictet–Spengler reaction, the product tetrahydro-β-carboline derivative
is obtained through imine formation followed by nucleophilic attack from the 2-position
of the indole ring, which is easy because of protonation of the imine in the acidic
media. The reason for the observed stereoselectivity using allyl-substituted sugar
aldehydes is not yet clear but it is possible that π-stacking interactions between
the allyl and the imine intermediate allows cyclization by electrophilic attack on
the 2-position of indole through a particular facial orientation. The involvement
of a remote allyl group in the mechanism of the reaction that increases the diastereoselectivity
of the process is a particularly unusual aspect of this methodology. For propyloxy
aldehyde, which is a saturated form of the allyloxy aldehyde that lacks allylic π-electrons,
the observed formation of two diastereoisomers supports the above conclusions.
Table 1 Chemical Shifts of C-1 and C-3 for Diastereoisomers
Diastereoisomer
13 C NMR (δ, ppm)
Stereochemistry
C-1
C-3
3a
52.95
42.91
3b
52.70
41.91
4a
56.27
52.80
cis
4b
52.97
51.02
trans
5a
53.87
49.80
trans
5b
56.52
52.78
cis
6a
52.97
41.71
6b
51.64
43.62
7a
53.87
48.39
trans
7b
a
56.20
53.91
cis
8
56.53
52.36
cis
9
54.25
48.65
trans
10
57.95
52.33
cis
11
54.55
50.55
trans
a Determined from 13 C NMR spectroscopic analysis of the crude reaction mixture.
On reduction by Pd/C (H2 ), diastereoisomer 9 gave only diastereomer 7a , confirming that no interconversion between diastereoisomers took place. We also
observed that all the major products have the same stereochemistry at C-1, which means
that nucleophilic attack during the imine stage favors a particular orientation. For
isomers 8 –11 , the presence of an allyl group and its participation in the π-stacking with the
imine occur in that orientation. Molecular model studies of the probable energy-minimized
imine intermediate[6a ]
[16 ] suggest it may adopt the conformation shown in Figure [1 ], in which the double-headed arrow indicates possible π-stacking above the plane,
and the attack (single-headed bent arrow) takes place from the below the plane.
Figure 1 Possible π-stacking interaction (indicated by double-headed arrow) in the allyl imine
intermediate and the favorable face of electrophilic attack on the 2-position of indole.
In summary, we have developed a straightforward and effective acid-catalyzed synthetic
route to tetrahydro-β-carboline glycosides. This process is regioselective and also
allows complete control over the stereochemistry at the C-1 and C-3 positions, depending
on the substituents present on the 4′-position of the sugar moiety. We believe that
π-stacking interactions direct the stereochemistry of the reaction and determines
the conformation of the products. The high stereoselectivity exhibited by this methodology
will be important for the preparation of a range of indole alkaloid intermediates.
Further work on this methodology with other substrates and its application to a broader
range of alkaloids towards new drug development is in progress.
