Practical and efficient preparation of the chiral 4-bromotryptophan derivative by Rh-catalyzed hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2019.151498

An efficient three-step sequence has been developed for the preparation of a chiral 4-bromotryptophan derivative starting from the commercially available 4-bromoindole. Key to the synthesis was the generation of the chiral center via a Rh-catalyzed asymme

Full text of DOI:10.1016/j.tetlet.2019.151498

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Practical and efficient preparation of the chiral 4-bromotryptophan derivative
by Rh-catalyzed hydrogenation
Nengjian Cai, Fen Mi, Yanmei Wu, Hao Song, Xiao-Yu Liu, Yong Qin
PII:
S0040-4039(19)31297-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151498
TETL 151498
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Tetrahedron Letters
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4 December 2019
5 December 2019
Please cite this article as: Cai, N., Mi, F., Wu, Y., Song, H., Liu, X-Y., Qin, Y., Practical and efficient preparation
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doi.org/10.1016/j.tetlet.2019.151498
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Graphical Abstract
Practical and efficient preparation of the
chiral 4-bromotryptophan derivative by Rh-
catalyzed hydrogenation
Leave this area blank for abstract info.
Nengjian Cai, Fen Mi, Yanmei Wu, Hao Song, Xiao-Yu Liu and Yong Qin

1
Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
Practical and efficient preparation of the chiral 4-bromotryptophan derivative by
Rh-catalyzed hydrogenation
Nengjian Cai, Fen Mi, Yanmei Wu, Hao Song, Xiao-Yu Liu and Yong Qin
a
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and
Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient three-step sequence has been developed for the preparation of a chiral 4-
bromotryptophan derivative starting from the commercially available 4-bromoindole. Key to
the synthesis was the generation of the chiral center via a Rh-catalyzed asymmetric
hydrogenation of a dehydrotryptophan precursor with 95% yield and >99% ee. Notably, the
whole synthetic route required no column chromatographic operations and was readily
conducted on large scales.
Available online
Keywords:
Asymmetric hydrogenation
Tryptophan
2
009 Elsevier Ltd. All rights reserved.
Indole alkaloid
Chiral ligand
4
Indole alkaloids represent a large family of natural products
with fascinating chemical structures and rich biological
activities. Tryptophan (1, Figure 1), the important starting point
associated analogues in enantiomerically pure forms. First, the
halogenate functionality at C4 could act as a synthetic handle for
the introduction of requisite groups. Second, the chiral
information bearing in these compounds would be transferred to
the final products via a substrate-controlled fashion.
1
in the biosynthesis of indole alkaloids, corresponds to the
“
indole•C N” building block that constitutes the key structural
2
2
units in these alkaloid molecules. As many complex indole
Several methods were previously documented in the literature
for the preparation of optically pure 4-halo-tryptophan
derivatives. These include, to name a few, an acylase-mediated
alkaloids contain varied substituents at the C4 position (e.g., 2–5,
3
Figure 1), the chiral 4-halotryptophan derivatives proved to be
important starting materials or synthetic intermediates for
accessing the corresponding indole alkaloid natural products and
5
4b,6
kinetic resolution approach, Pd-catalyzed annulation
or Ni-
4d
catalyzed reductive cross-coupling protocols using chiral
starting materials, as well as an alkylation strategy with a proline-
based chiral auxiliary. Asymmetric catalysis based on transition
metals has proved to be efficient tools for the generation of chiral
4
f
7
molecules. In 1995, Yokoyama and co-workers described the
synthesis of a chiral 4-bromotryptophan derivative 7 by
asymmetric reduction of the corresponding dehydrotryptophan
precursor 6 with the best ee value of 94% using DIPAMP
8
phosphine ligand (Scheme 1A). Not only the enantioselectivity
of the key hydrogenation reaction was not perfect, but
preparation of the 4-bromodehydrotryptophan substrate
6
8
required
a
stoichiometric amount of Pd(OAc)2, which
significantly reduced the overall synthetic efficiency. Thus, a
simple and efficient method for synthesizing the chiral 4-
bromotryptophan derivative is still desirable. Herein, we report
an operationally simple and scalable synthesis of the chiral 4-
bromotryptophan 9 employing a Rh-catalyzed asymmetric
Figure 1. Selected indole alkaloids containing C4 functionalities.
—
——


Corresponding author. e-mail: xyliu@scu.edu.cn
Corresponding author. e-mail: yongqin@scu.edu.cn

2
Tetrahedron
hydrogenation as the key step. The use of DuanPhos as the
chiral ligand allowed the generation of 9 with excellent yield
95%) and enantiomeric purity (>99%) (Scheme 1B).
methylallyl) (COD) (1 mol%) and (R)-SDP (L1, 1.1 mol%) in
2
EtOH under the atmosphere of H (10 bar) at room temperature
2
(
afforded the desired reduction product 9 with full conversion of
the starting material and with 21% ee (entry 1). Different ligands
L2–L4 (entries 2–4) were unsuccessful to improve the reaction
enantioselectivity. Subsequently, we switched the metal catalyst
to Rh(NBD) BF that was commonly used in the reduction of
2
4
1
2
enamide substrates. Extensive screening of various chiral
ligands (entries 5–13) was then conducted under the atmosphere
of H (50 bar). Specifically, many ligands including (R)-BINAP
2
(
L3), (R)-SDP (L1), (Ra,S)-DTB-Bn-SIPHOX (L5), (2S,3R)-
MeO-POP (L2), (S,S)-DIOP (L6), (2S,2’S,3S,3’S)-MeO-BIBOP
L7), and (R,S )-BoPhoz (L8) only led to low conversion and
(
P
unsatisfactory enantioselectivity (entries 5–11). By contrast, we
were delighted to find that (R ,S )-DuanPhos (L4) was perfect to
C
P
deliver a spot-to-spot conversion and excellent ee value (>99%)
1
3
of the product (entry 12). Of note, use of DIPAMP as the chiral
ligand under the same conditions failed to generate any desired
8
,14
product (entry 13). The effect of different anions for the Rh-
catalyst was also surveyed (entries 14–16) and all the attempted
anions gave inferior results compared to BF (entry 12).
4
a
Table 1. Exploration and optimization of the reaction conditions
Scheme 1. Catalytic asymmetric hydrogenation approaches to chiral
4
-bromotryptophan derivatives.
H
2
conv.
(%)
ee
Our synthetic efforts commenced with the preparation of the 4-
entry
catalyst
ligand
b
c
(bar)
(%)
21
<5
25
13
<5
25
18
---
<5
31
38
>99
---
94
90
90
bromodehydrotryptophan substrate 8 (Scheme 2). According to a
d
9
1
2
3
4
Ru(2-methylallyl)
Ru(2-methylallyl)
Ru(2-methylallyl)
Ru(2-methylallyl)
Rh(NBD)
Rh(NBD)
Rh(NBD)
Rh(NBD)
Rh(NBD)
Rh(NBD)
Rh(NBD)
Rh(NBD) BF4
Rh(NBD)
Rh(NBD) SbF6
Rh(NBD)
Rh(NBD)
2
2
2
2
(COD)
(COD)
(COD)
(COD)
L1
L2
L3
L4
L3
L1
L5
L2
L6
L7
L8
L4
DIPAMP
L4
L4
10
10
10
10
50
50
50
50
50
50
50
50
50
50
50
50
100
100
100
100
17
30
26
trace
57
60
known procedure, 4-bromoindole (10) was first treated with
d
d
POCl /DMF followed by reflux in aqueous KOH to give
3
d
aldehyde 11 with quantitative yield. Based on a protocol reported
1
0
5
6
7
8
9
2
2
2
2
2
2
2
BF
BF
BF
BF
BF
BF
BF
4
4
4
4
4
4
4
by Jursic and colleagues, aldehyde 11 was condensed with an in
situ generated oxazolone intermediate (not shown) from N-
benzoylglycine (12) in the presence of NaOAc/Ac O, leading to
2
the coupling product 13. Subjection of the crude 13 to the
conditions of NaOMe in methanol at room temperature resulted
in opening of the oxazolone ring and afforded the desired ,-
unsaturated tryptophan 8 with 73% overall yield (11→8).
1
1
0
1
25
12
13
14
2
100
NR
86
38
65
2
BF
4
8
2
Compared to the previously known methods, the above-
1
1
a
5
6
2
PF
CO
6
mentioned protocol was more efficient that avoided the use of
transition metals and column chromatographic operations. Thus,
this practical approach easily provided us decagram materials of
-bromodehydrotryptophan 8, setting the stage for investigating
the catalytic asymmetric reduction of the enamide double bond.
2
2
CF
3
L4
Unless otherwise specified, all reactions were performed with 0.25 mmol of 8
in the presence of catalyst (1 mol%) and ligand (1.1 mol%) at room
temperature for 20 h. NBD = 2,5-norbornadiene, COD = cyclooctadienyl.
Obtained according to HPLC analysis of the crude reaction mixture.
Determined by HPLC using a Chiralcel OD-H column. These reactions were
4
b
c
d
4 2
carried out in the presence of HBF •Et O (2 mol%) using EtOH as the reaction
solvent.
With the optimal catalyst/ligand combination, we performed a
scale-up reaction (Scheme 3) and found that the reaction yield
Scheme 2. Practical synthesis of 4-bromodehydrotryptophan 8.
(95%) and enantioselectivity (>99%) maintained on a 5.0 gram
scale experiment with less Rh(NBD) BF (0.5 mol%) and L4
With 8 in hand, we set out to examine the reaction conditions
for the catalytic asymmetric reduction of the enamide double
bond (Table 1). The relatively cheap catalyst Ru(2-
2
4
(0.55 mol%) at a slightly elevated temperature (50 ºC). Simple
and direct recrystallization from the reaction mixture (in
methanol) provided 4.75 g of the desired 4-bromotryptophan
derivative 9.
1
1
methylallyl) (COD) was employed in the initial experiments.
2
Subjecting the ,-unsaturated tryptophan
8
to Ru(2-

3
5
6
.
.
Y. Yokoyama, K. Osanai, M. Mitsuhashi, K. Kondo, Y.
Murakami, Heterocycles 55 (2001) 653–659.
(a) Y. Jia, J. Zhu, Synlett 16 (2005) 2469–2472. (b) Y. Jia, J. Zhu,
J. Org. Chem. 71 (2006) 7826−7834. (c) Z. Xu, W. Hu, F. Zhang,
Q. Li, Z. Lü, L. Zhang, Y. Jia, Synthesis 24 (2008) 3981–3987. (d)
Z. Xu, Q. Li, L. Zhang, Y. Jia, J. Org. Chem. 74 (2009) 6859–
6
862. (e) Z. Xu, F. Zhang, L. Zhang, Y. Jia, Org. Biomol. Chem. 9
(
2011) 2512–2517.
Scheme 3. Gram scale catalytic asymmetric hydrogenation of 8.
7
8
.
.
H.U. Blaser, H.-J. Federsel, Asymmetric Catalysis on Industrial
Scale: Challenges, Approaches and Solutions, Wiley-VCH,
Weinheim, 2010.
To summarize, we have developed a practical and scalable
synthetic approach to the optically pure 4-bromotryptophan
derivative 9 starting from the commercially available 4-
bromoindole (10) in three steps with 69% overall yield and
without use of any column chromatographic operations. Among
these steps, a key Rh-catalyzed asymmetric hydrogenation
employing DuanPhos as the chiral ligand furnished the expected
product 9 with excellent ee (>99%), which, to the best of our
knowledge, represents the highest enantioselectivity obtained in
the asymmetric hydrogenation of such dehydrotryptophan
substrates. Predictably, the present method would be able to
facilitate the asymmetric synthesis of related indole alkaloids and
analogues. Such efforts are ongoing in our laboratory and will be
reported in due course.
Y. Yokoyama, T. Matsumoto, Y. Murakami, J. Org. Chem. 60
(1995) 1486−1487.
9. E. Michael, C.A. Muratore, A.W. Holloway, R. Pilling, S. Ian, T.
Graham, J.D. Darren, J. Am. Chem. Soc. 131 (2009) 10796–
1
0. B.S. Jursic, S. Sagiraju, D.K. Ancalade, T. Clark, E.D. Stevens,
Synth. Commun. 37 (2007) 1709–1714.
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Asymmetry 2 (1991) 43−46.
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Zhang, Org. Lett. 6 (2004) 3565−3567. (b) W. Jeroen, J.N.H.
Reek, J. Org. Chem. 74 (2009) 8403−8406. (c) W. Tang, A.G.
Capacci, A. White, S. Ma, S. Rodriguez, B. Qu, J. Savoie, N.D.
Patel, X. Wei, N. Haddad, N. Grinberg, N.K. Yee, D.
Krishnamurthy, C.H. Senanayake, Org. Lett. 12 (2010) 1104-
0797.
1
1
1
1
107. (d) A. Inmaculada, A. Eleuterio, P. Antonio,
Organometallics 32 (2013) 2497−2500. (e) Q. Wang, W. Huang,
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Acknowledgments
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21871189) and
National Major Science and Technology Projects of China
(2016) 40−43. (h) W. Gao, H. Lv, X. Zhang, Org. Lett. 19 (2017)
2
877−2880. (i) Y. Guan, S.E. Wheeler, Angew. Chem. Int. Ed. 56
(2017) 9101−9105. (j) G. Li, O.V. Zatolochnaya, X.-J. Wang, S.
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D. Rivalti, S.D. Karyakarte, J.D. Sieber, N. Grinberg, L. Wu, H.
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References and notes
1
3. The absolute configuration of the generated stereocenter in 9 was
assigned as (R) by comparison of its CD spectrum with that of a
debromo compound derived from L-tryptophan. See the
Supplementary data for details.
1
.
J. Buckingham, K.H. Baggaley, A.D. Roberts, L.F. Szabó,
Dictionary of Alkaloids; CRC Press: Boca Raton, 2nd edn, 2010;
pp lvii–lxvi.
2
3
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P.M. Dewick, Medicinal Natural Products:
Approach, Third Edition, Wiley, 2009.
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A
Biosynthetic
14. Subjecting 4-bromodehydrotryptophan 8 to the same asymmetric
hydrogenation conditions as those reported by Yokoyama et al
(ref. 8) resulted in no reaction over 96 h.
1
(
1
269−1274. (b) W.A. Jacobs, L.C. Craig, J. Biol. Chem. 104
1934) 547−551. (c) J.E. Robbers, H.G. Floss, Tetrahedron Lett.
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Supplementary Material
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Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
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4
.
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89−206.

4
Tetrahedron
A practical and scalable synthesis of a chiral 4-

bromotryptophan derivative in three steps


A key Rh-catalyzed asymmetric hydrogenation with
excellent enantioselectivity (>99%)
Column-chromatography-free in the whole synthetic
route