Unprecedented Stereocontrol in the Synthesis of 1,2,3-Trisubstituted Tetrahydro-β-carbolines through an Asymmetric Pictet–Spengler Reaction towards Sarpagine-Type Indole Alkaloids

Article abstract of DOI:10.1002/ejoc.201800600

The asymmetric Pictet–Spengler (P-S) reaction of chiral N_b-ethynyl-substituted tryptophan methyl ester derivatives (from both d- and l-tryptophan) with a simple aliphatic aldehyde, exhibited unprecedented selectivity towards either of the diastereomeric products. A simple variation of conditions could alter the outcome of the cyclization from either 100 % trans-selective to 100 % cis-selective originating entirely from internal asymmetric induction under mild conditions. This resulted in a highly efficient access to both 1,3-cis-(1,2,3-trisubstituted tetrahydro-β-carbolines, THβCs) and 1,3-trans-(1,2,3-trisubstituted THβCs). To the best of our knowledge, this type of stereocontrol has never been observed from tryptophan methyl ester derivatives (either D or L) in accessing either 1,3-disubstituted or 1,2,3-trisubstituted THβCs. By exploiting this very useful ambidextrous diastereoselectivity, we have set the crucial C-3 and C-5 stereocenters of C-19 methyl-substituted sarpagine/macroline/ajmaline alkaloids beginning with the DNA-encoded and cheaper l-(–)-tryptophan, as well as optionally from commercially available d-(+)-tryptophan.

Full text of DOI:10.1002/ejoc.201800600

A Journal of
Accepted Article
Title: Unprecedented stereocontrol in the synthesis of 1,2,3-
trisubstituted tetrahydro-β-carbolines via a new asymmetric Pictet
—Spengler reaction towards sarpagine-type indole alkaloids
Authors: Md Toufiqur Rahman and James M. Cook
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800600
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800600
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10.1002/ejoc.201800600
European Journal of Organic Chemistry
COMMUNICATION
Unprecedented stereocontrol in the synthesis of 1,2,3-
trisubstituted tetrahydro-β-carbolines via a new asymmetric
Pictet—Spengler reaction towards sarpagine-type indole
alkaloids
M. Toufiqur Rahman and James M. Cook*
Abstract: The asymmetric Pictet-Spengler (P-S) reaction of chiral Nb-
the preparation of 1,3-disubstituted THβCs.[5b, 5c, 6a, 8g, 8h, 9] In the
case of 1,3-disubstituted THβC, Bailey, Sato, Misicka, and Shi
have made notable advances in devising a cis-selective P-S
reaction to gain access to the cis-1,3-disubstituted THβC system
(see SI, Scheme S-1). These strategies are logical in a chemical
sense because of their promise to access the C-3 stereochemistry
of indole alkaloids, starting from L-tryptophan. The requirement of
pi-systems either at C-1 or C-3 however, is not desirable since
very often these esters or aldehyde equivalents are surprisingly
hard to prepare and require special processes for removing them.
Moreover, often the products are not useful toward the synthesis
of alkaloids which would require complex transformations. To the
best of our knowledge, completely cis-selectivity in the P-S
reaction with tryptophan methyl esters and aliphatic aldehydes
have not been reported yet.
ethynyl substituted tryptophan methyl ester derivatives (from both D-
and L-tryptophan) with
a simple aliphatic aldehyde, exhibited
unprecedented selectivity towards either of the diastereomeric
products. A simple variation of conditions could alter the outcome of
the cyclization from either 100% trans-selective to 100% cis-selective
originating entirely from internal asymmetric induction under mild
conditions. This resulted in a highly efficient access to both 1,3-cis-
(1,2,3-trisubstituted tetrahydro-β-carbolines, THβCs) and 1,3-trans-
(1,2,3-trisubstituted THβCs). To the best of our knowledge, this type
of stereocontrol has never been observed from tryptophan methyl
ester derivatives (either D or L) in accessing either 1,3-disubstituted
or 1,2,3-trisubstituted THβCs. By exploiting this very useful
ambidextrous-diastereoselectivity, we have set the crucial C-3 and C-
5 stereocenters of C-19 methyl substituted sarpagine-macroline-ajm-
aline alkaloids beginning with the DNA-encoded and cheaper L-(-)-
tryptophan, as well as optionally from commercially available D-(+)-
tryptophan.
On the other hand, for 1,2,3-trisubstituted THβC systems, the
P-S reaction of Nb-benzylated tryptophan methyl esters (e.g., 1)
with aldehydes or acetals (e.g., 2) is well known for complete
trans-selectivity under thermodynamic conditions yielding 1,3-
trans-1,2,3-trisubstituted THβCs 3 (Scheme 1, entry 1).[1a] This
robust strategy has been employed on up to 600 gram scale
processes and in excellent diastereo (100% de) and
enantioselectivity (up to 98% ee) in excellent yield, while avoiding
chromatographic purification. The syntheses of numerous indole
and oxindole alkaloids with potent biological activity have utilized
this trans-specific method.[10] Many examples of the preparation
of 1,2,3-trisubstituted THβCs are present in the literature via
The Pictet-Spengler (P-S) reaction of tryptophan derivatives
with an aldehyde other than formaldehyde results in two
diastereomeric THβCs (at C-1 and C-3 of the THβC, see Scheme
1). The THβC moiety deserves special attention in its own right as
it is at the core of numerous bioactive alkaloids, as well as
medicinally important synthetic analogs. As a consequence
numerous studies accessing this moiety by various strategies
have been undertaken.[1] Almost all useful compounds containing
the THβC core (both natural and synthetic) bear a stereocenter at
C-1. On the other hand, in the vast majority of the
sarpagine/ajmaline-type alkaloids, there is cis-1,3-disubstitution
in the THβC core (cis-3,5 of alkaloids in Figure 1). As a result, the
diastereoselectivity of the P-S reaction to access the 1,3-cis-
THβC core is of special importance. Numerous attempts have
been made to gain control in the selectivity in this process by
varying the temperature, solvent, chiral catalysts, chiral reactive
partners (including chiral aldehyde equivalents), and different
tryptophan alkyl esters, etc.[1a, 2]
thermodynamic control to give mostly (if not exclusively), trans-
8i, 8k]
1,3-disubstitution.[8e,
To the best of our knowledge, cis-
specificity in preparing 1,2,3-trisubstituted THβCs from tryptophan
alkyl esters is absent in the literature. Herein, we report
unprecedented stereocontrol in cis- and trans-selectivity in
accessing 1,2,3-trisubstituted THβCs from chiral Nb-ethynyl
substituted tryptophan derivatives
4 with simple aliphatic
aldehydes 5 to furnish either completely the cis-diastereomer 6 or
the trans-isomer 7, controlled by simple changes in reaction
conditions (Scheme 1, entry 2). This strategy will greatly improve
the approach towards the total synthesis of either the (+) or (-)
enantiomer of a group of more than thirty sarpagine/macroline-
/ajmaline indole alkaloids. Depicted in Figure 1 are a few
representative examples (8-13)[11] from this group of bioactive
alkaloids (for more examples see the SI, Figure S-1). Furthermore,
the complete cis-selectivity would permit the synthesis to begin
with the natural and cheaper L-tryptophan methyl ester instead of
D-tryptophan methyl ester which has been used previously. In this
version of the P-S reaction, it is the ability to prepare both the (+)
or (-) enantiomer of these indole alkaloids from either D-(+)-
tryptophan or L-(-)-tryptophan is of significance and illustrated
here for the first time.
The asymmetric P-S reaction has undergone elegant
advances by Jacobsen,[3] Nakagawa,[4] Bailey,[5] Misicka,[6]
Hiemstra,[7] Van Maarseveen,[7] List,[8] and many others.[8] Cis-
Selectivity in the asymmetric P-S reaction has been reported in
Department of Chemistry and Biochemistry
University of Wisconsin-Milwaukee
3210 N Cramer Street, Milwaukee, WI-53201
E-mail: capncook@uwm.edu
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
Recently, we published the total synthesis of a number of
sarpagine-related bioactive indole alkaloids via a better and sh-
in several hours instead of several days. It is felt, the amine 4a
reacts with the aldehyde 5 in the presence of AcOH to form the
kinetic product (cis-diester, 6a) while acetic acid is not acidic
enough to facilitate cleavage of the C(1)-N(2) bond which
normally provides only the trans-diastereomer.[14] Conversely,
when the kinetic product (i.e., 6a) was treated with TFA in DCM,
the cis-diastereomer rearranged completely to the thermod-
ynamic product (i.e., the trans-product 7a). To the best of our
knowledge, this type of selectivity in the formation of completely
cis- or trans-THβC from a single tryptophan derivative has never
been seen in the formation of the 1,2,3-trisubstituted THβC-
system.
orter route for accessing the core-tetracyclic intermediates
employing an improved P-S strategy.[12] One of the principal goals
of that study was to gain quicker access to the key-intermediates,
improving the previous strategy, and developing a shorter route
to the tetracyclic-core required for an important group of more
than thirty[10c, 13] alkaloids. Several interesting observations were
noted in the P-S/Dieckmann protocol.[12a] When D-tryptophan
methyl ester derivative with an Nb-ethynyl substituent bearing a
methyl group with the (S) stereochemistry (4a) reacted with acetal
2 in acidic media (TFA in DCM), excellent diastereoselectivity
(>95:5) towards the trans-diester (7a) was observed (not shown
here).[12a] On the other hand, when the reaction of the tryptophan
methyl ester derivative with the (R)-methyl substituent (4d) was
stirred under the same conditions, this resulted in a complex
reaction mixture. Afterwards, it was discovered milder reaction
conditions using the aldehyde 5 and acetic acid instead of the
acetal 2 and trifluoroacetic acid altered the chemistry. The
asymmetric P-S reaction of the amine 4d with aldehyde 5
proceeded smoothly under the modified and milder conditions to
provide a 70 to 30 mixture of cis to trans-diastereomers in 95%
combined isolated yield (Scheme 2).[12a] The excellent overall
yield and diastereoselectivity towards the cis-diester captured our
attention. A further investigation of this reaction, in order to find
conditions for better selectivity became the focus. As a step
toward this, the same conditions were applied to Nb-(S)-methyl-
ethynyl substituted tryptophan derivative (4a). To our surprise, the
reaction was complete in 10 hours and provided the cis-diester 6a
with 100% cis-diastereoselectivity. The addition of 3 equivalents
of TFA after the initial P-S reaction (at 10 hours), converted the
cis-diester 6a completely into the corresponding trans-diester 7a
(Scheme 2). Furthermore, addition of 4 Å molecular sieves to the
reaction had, as expected, a tremendous effect on the rate.
Reactions run in the presence of molecular sieves were complete
Encouraged by the unprecedented outcome of the P-S
reaction, it was felt of importance to investigate the underlying
reason(s) for this ambidextrous-diastereoselectivity. It was
obvious exploitation of complete cis-selectivity would permit the
synthesis of sarpagine alkaloids with the cheaper and natural L-
(-)-tryptophan, instead of D-(+)-tryptophan. The optically pure
tosylate units (18a-d) required for amines 4a-i were synthesized,
as depicted in Scheme 3 (see note 16 and SI).
The synthesis of amine-substrates (4a-i) for the P-S reaction
were performed, as shown in Scheme 4. With all the required
substrates in hand, the planned reactions were performed with 1
equivalent of the amines, 1.5 equivalents of the aldehyde, 3
equivalents of acetic acid, 200 mg 4 Å MS (per mmol of amines).
The reactions were performed parallel at 0 oC and at rt. The
outcome of these experiments are listed in Table 1. These
reaction processes gave excellent overall isolated yields (up to
95%) with selectivity towards cis-diesters. All the cis- and trans-
diester products were easily separable by silica gel column
chromatography except for (entry 6) where both of them had the
same Rf in several solvent systems. Interestingly, some clear
patterns emerged. For example, when the carbon atoms a and b
had the same configurations (S,S) or (R,R) (Table 1, entries 2, 4,
6, and 8), reactions were up to 82% cis-selective. The cis-
selectivity improved at lower temperature (e.g., Table 1, entries 2,
8) and the bulky TIPS containing amines exhibited better cis-sele-
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COMMUNICATION
Table 1. P-S reaction of amines 4a-i with aldehyde 5
c: t (0)d
ya
(%)
entry
amine-substrate
c: t
(rt)e
R1
R3
a
b
1
2
3
4
5
6
4a
4d
4b
4e
4c
4i
TIPS
H
H
H
H
H
H
H
R
S
100:0
72:28
100:0
43:57
100:0
58:42b
100:0
100:0
65:35
100:0
50:50
100:0
90
95
82
84
85
78
TIPS
TMS
TMS
H
H
H
H
H
H
R
R
R
R
R
R
S
R
S
R
c
H
-
ctivity (compare entry 2 and 8 vs 4 and 6 in Table 1) than amines
which contained a TMS- or H-substitution. Interestingly, on the
other hand, when the configurations of carbon atoms a and b
were opposite to each other i.e., (R,S) or (S,R), reactions were
100% cis-selective regardless of temperature, and size of the
alkyne protecting groups (TIPS, TMS and H), as indicated by
entries 1, 3, 5, 7, and 9. As expected, the P-S reaction with an
electron rich tryptophan (4f, 5-MeO) reacted faster. The C-5 ring-
A oxygen function, however, had no effect on the outcome of the
diastereoselectivity other than speeding up the rate. Similarly, the
same pattern was observed with the L-(-)-tryptophan derivatives
(entries 8-9). More importantly, all of the diastereomers could
easily be separated and the pure, isolated cis-diesters could be
converted into the corresponding trans-diesters (100% de),
simply by treatment with TFA in DCM for 2-20 hours at room
temperature (see SI for details).
7
4f
TIPS OMe Me
R
S
100:0
85
8
9
4g
4h
TIPS
TIPS
H
H
H
H
S
S
S
R
82:18
100:0
72:28
100:0
85
88
aIsolated yields; bboth cis and trans isomer had the same Rf, and were isolated after
complete conversion into the trans-diester; cnot done; cis: trans at d0 oC; eroom temp.
Consequently, conditions were designed for selective
generation of either the trans- or the cis-diesters from either D(+)-
or L(-)-tryptophans. It is well-known that plants or natural sources
generally produce one enantiomer of the chiral natural products.
Due to this, it is possible to isolate and screen for bioactivity only
one of the enantiomers. Logically, the unnatural enantiomer might
actually be as good as the natural enantiomer or even better in
activity as well as in toxicity profile depending on metabolism. The
development of the life-saving anti-HIV/AIDS drug emtricitabine
by Professor Liotta at Emory, exemplified the tremendous
potential of unnatural enantiomers of bioactive molecules in drug
discovery.[15] As depicted in Scheme 5, the 3,5-cis-disubstitution
(biogenetic numbering, 24 and 25) of the natural enantiomer of
sarpagine/macroline alkaloids could be furnished either from
28 and 30, starting from L-tryptophan derivative 21 were
undertaken. The β-ketoesters 28, and 30 are key intermediates
for the total synthesis of a group of sarpagine-related indole
alkaloids and were employed previously in total synthesis and
were synthesized from D-(-)-tryptophan methyl ester.[12a] As
shown in Scheme 6, the cis-diester 29 was synthesized from L-
(+)-tryptophan methyl ester 21 via Nb-alkylation (4h) and the cis-
specific P-S reaction (100% cis, Table 1, entry 9). The cis-diester
29 upon Dieckmann cyclization provided the β-ketoester 28 in
excellent yield. The ester 28 was previously synthesized from (-)-
19.[12a] The indoles from both routes were identical in all respects
natural L-tryptophan via
a cis-selective P-S reaction or
alternatively from D-tryptophan via a trans-selective P-S reaction.
Conversely, the unnatural enantiomer of these alkaloids would
also be accessible either from L-tryptophan via a trans-selective
P-S reaction (26 and 27) or alternatively from D-tryptophan via a
cis-selective P-S reaction (see Scheme 5 for details). This novel
ambidextrous approach to the synthesis of both the natural and
unnatural enantiomers of bioactive sarpagine-type alkaloids
would permit the rapid screening of the biological activity of both
of the enantiomers. To illustrate the usefulness of this method, the
synthesis of key intermediates for natural product synthesis,[12a]
1
(Rf, H NMR, and 13C NMR), as well as the optical rotation (see
Scheme 6, note 17, and SI). This enabled one to access the same
group of indole alkaloids starting from L-tryptophan via the
unprecedented cis-specific P-S reaction reported herein (Scheme
6).
Similarly, the β-ketoester 30 could be prepared form D-trypto-
phan via 7a (100% trans-selective P-S reaction, which was >95%
previously[12a]), as depicted in Scheme 7. Importantly the same β-
ketoester 30 could be synthesized from (+)-21 via a cis-selective
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COMMUNICATION
f)J. Stöckigt, A. P. Antonchick, F. Wu, H. Waldmann, Angew. Chem. Int.
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(82% cis) P-S reaction. The spectral properties of (-)-30 from both
(+)-21 and (-)-19 are identical in all respects (Scheme 7).
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In summary, we have developed a novel strategy to gain
access to the 1,2,3-trisubstituted THβCs with the required C-3/C-
5 stereochemistry of a group of sarpagine-related indole alkaloids
with unprecedented control of the asymmetric P-S reaction. This
report also illustrates the ability to achieve the complete cis-
selectivity of the PS reaction to form the 1,2,3-trisubstituted THβC
by internal asymmetric induction. Key intermediates [(+)-28 and
(-)-30] towards the total synthesis of a group of thirty C-19 methyl
substituted alkaloids have been accessed from the natural and
cheaper L-(-)-tryptophan now instead of the previously developed
route from D-(+)-tryptophan. This permits the synthesis of either
enantiomer from the same THβC branching point.
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Acknowledgements
We thank the NIH (NS076517, MH096463) for generous
financial support and the Shimadzu Analytical Laboratory of
Southeastern Wisconsin for mass spectroscopy.
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[15] D. C. Liotta, G. R. Painter, Acc. Chem. Res. 2016, 49, 2091-2098.
[16]
[17]
a)
b)
Figure 1. Comparison between the (a) 1H and (b) 13C NMR spectra of (+)-28
from L-tryptophan (red) and D-tryptophan (blue) as shown in Scheme 6
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