Synthesis of d -abrines by palladium-catalyzed reaction of ortho-iodoanilines with N -Boc- N -methylalanyl-substituted acetaldehyde and acetylene

Article abstract of DOI:10.1021/ol4009409

A novel strategy to N-Boc-N-methyl - tryptophans (abrine derivatives) was developed that relies on the palladium-catalyzed annulation of ortho-iodoanilines 12 with either N-Boc-N-methyl-propargylglycine 16 or aldehyde 11. Both 11 and 16 can be prepared from d-serine. An alternative route to propargylglycine 16 utilizes an enantioselective propargylation reaction of glycine imine 17.

Full text of DOI:10.1021/ol4009409

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Synthesis of D‑Abrines by Palladium-
catalyzed Reaction of ortho-Iodoanilines
with N‑Boc‑N‑methylalanyl-substituted
Acetaldehyde and Acetylene
000–000
Paulami Danner, Marius Morkunas, and Martin E. Maier*
Institut f u€ r Organische Chemie, Universit a€ t T u€ bingen, Auf der Morgenstelle 18,
7
2076 T u€ bingen, Germany
martin.e.maier@uni-tuebingen.de
Received April 5, 2013
ABSTRACT
A novel strategy to N-Boc-N-methyl–tryptophans (abrine derivatives) was developed that relies on the palladium-catalyzed annulation of ortho-
iodoanilines 12 with either N-Boc-N-methyl-propargylglycine 16 or aldehyde 11. Both 11 and 16 can be prepared from D-serine. An alternative route
to propargylglycine 16 utilizes an enantioselective propargylation reaction of glycine imine 17.
A common feature of post-translationally modified pep-
tides and depsipeptides is the presence of N-methylated
amino acids. Frequently such amino acids occur in the less
commonly encountered D-configuration. This simple mod-
ification can influence the conformation, protect the corre-
sponding peptide bond toward attack by proteases and
change the hydrogen bonding pattern compared to the
nonmethylated analogue. A prominent example is N-methyl
tryptophan, also called abrine. It can be found in the
then to methylate the dianion, for example with NaH/CH I
3
3,4
in DMF. However in the case of tryptophan this strategy
requires protection of the indole NH prior to the N-methyla-
5
tion step. The same is true for other side chain functionalized
amino acids. An alternative that avoids protection of the
indole NH is via sequential reductive amination, first with
benzaldehyde then with paraformaldehyde, followed by
debenzylation through catalytic hydrogenation and urethane
6
formation. In addition, the reduction of formamide deriva-
7
tives has been used as a means of N-methylation.
1
2
cyclodepsipeptides jasplakinolide 1 and the chondramides
2
À5 (Figure 1). These are natural products that target the
In connection with the synthesis of chondramide A analo-
gues, we required several D-abrine derivatives modified in
the indole ring. We wondered whether some of the known
convergent strategies to tryptophans might be adaptable to
actin skeleton.
A classical route to N-methylamino acids is to start from
the amino acid, protect the amino group as a carbamate and
(
5) (a) Grieco, P. A.; Hon, Y. S.; Perez-Medrano, A. J. Am. Chem. Soc.
(
1) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27,
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1988, 110, 1630–1631. (b) Hirai, Y.; Yokota, K.; Momose, T. Heterocycles
1994, 39, 603–612. (c) Ashworth, P.; Broadbelt, B.; Jankowski, P.;
Kocienski, P.; Pimm, A.; Bell, R. Synthesis 1995, 199–206.
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M.; Tanaka, T. Chem. Lett. 1984, 13, 441–444. (b) White, K. N.;
Konopelski, J. P. Org. Lett. 2005, 7, 4111–4112. (c) Tannert, R.; Milroy,
L.-G.; Ellinger, B.; Hu, T.-S.; Arndt, H.-D.; Waldmann, H. J. Am. Chem.
Soc. 2010, 132, 3063–3077.
(7) Chu, K. S.; Negrete, G. R.; Konopelski, J. P. J. Org. Chem. 1991,
56, 5196–5201.
(8) For a review about synthesis of indoles via palladium-catalyzed
reactions, see: Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215–PR283.
2
(
J. Antibiot. 1995, 48, 1262–1266. (b) Jansen, R.; Kunze, B.; Reichenbach,
H.; H o€ fle, G. Liebigs Ann. 1996, 285–290.
(
3) See, for example: (a) Cheung, S. T.; Benoiton, N. L. Can. J. Chem.
977, 55, 906–910. (b) Aurelio, L.; Box, J. S.; Brownlee, R. T. C.;
Hughes, A. B.; Sleebs, M. M. J. Org. Chem. 2003, 68, 2652–2667.
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Chem. 2009, 74, 8425–8427.
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Chem. Rev. 2004, 104, 5823–5846.
1
(
(
1
0.1021/ol4009409 r XXXX American Chemical Society

Scheme 1. Synthesis of Methyl 5-Oxopentanoate 11 and its
Coupling with Iodoaniline 12a to Give D-Abrine 13a
Figure 1. Structures of jasplakinolide (1) and the chondramides
2À5).
(
8
the direct synthesis of abrine derivatives. In this paper
we show that this is indeed possible through coupling of
ortho-iodoanilines with a functionalized alkyne or aldehyde
building block that already contains the N-methylated amino
acid sector.
the N-methylation an excess of both silver(I) oxide (4 equiv)
and methyl iodide (16 equiv) were used. Under these
conditions, N-Boc-N-methyl homoallylglycine methyl
ester 10 was obtained in 95% yield, essentially without any
racemization. Subsequent dihydroxylation of the double
bond followed by oxidative cleavage of the diol furnished
13
aldehyde 11 in reasonable yield.
The crucial domino sequence consisting of enamine
formation between iodoaniline 12a (1.3 equiv) and alde-
hyde 11 (1 equiv), followed by Heck cyclization, was
One plan was to use the palladium catalyzed annulation
between iodoanilines and chiral aldehyde 11. The group of
Zhu has already shownthatthisindolesynthesis, originally
1
2
9
developed by Chen, works with N,N-di-tert-butoxycar-
1
0
bonyl-5-oxopentanoate. With a free NH, this reaction
proceeded in low yield, probably due to internal hemiam-
inal formation.
First, homoallyl glycine 9 was prepared from D-serine
6), which was converted to N-Boc serine methyl ester and
(
from there to iodide 7, following published procedures.
performed using the optimized conditions [Pd(OAc) ,
2
1
1
9
DABCO, DMF, 100 °C] of Zhu. In this way, D-abrine
The derived organozinc reagent 8 was then coupled with
allyl chloride in presence of copper bromide to give
homoallylglycine 9. For success in this coupling reaction,
a solution of iodide 7 should be slowly added to zinc dust,
activated by preheating, under a nitrogen atmosphere at
13a was obtained in 51% yield. The optical purity of 13a
was checked by chiral HPLC, which indicated an ee
of >99% (Scheme 1).
On the basis of these results, several other D-abrines were
prepared from iodoanilines 12bÀeand aldehyde 11 (Table 1).
The chemical yields for these coupling reactions were in the
range of 38À51%. While occurring with moderate yields,
this coupling method provides direct access to the final N-
methylated tryptophan analogues 13. The optical purity
was determined by chiral HPLC for tryptophan 13a, which
turned out to be very high. This indicated that the coupling
conditions did not cause racemization of the chiral center.
Another strategy to convert ortho-iodoanilines to indoles
relies on the so-called Larock coupling where disubstituted
alkynes are used for a palladium-catalyzed annulation
0
°C. After the addition, the cooling bath should be
removed and stirring continued for 2 h. After the insertion,
the supernatant solution containing the organozinc re-
agent needs to be added slowly to a solution of copper
bromide and allyl chloride in DMF at À15 °C. Thereafter,
the mixture is stirred overnight at ambient temperature.
Initially we performed the N-methylation of amino acid
9
with NaH/CH I in DMF. However, as it turned out,
3
these conditions led to partial racemization (roughly 3:1
ratio of the enantiomers). Better results were obtained
4
with the reagent combination Ag O/CH I in DMF. For
2
3
(
12) The optical purity of amino acid derivative 10 was assessed by
chiral HPLC after cleavage of the Boc group and conversion of the
amine to the corresponding 2,4,6-trichlorobenzamide derivative, see
Supporting Information.
(
9) Chen, C.-y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1997, 62, 2676–2677.
(
(
10) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826–7834.
11) (a) Rodriguez, A.; Miller, D. D.; Jackson, R. F. W. Org. Biomol.
(13) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217–3219.
Chem. 2003, 1, 973–977. (b) Huber, T.; Manzenrieder, F.; Kuttruff, C. A.;
Dorner-Ciossek, C.; Kessler, H. Bioorg. Med. Chem. Lett. 2009, 19,
(14) (a) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998,
63, 7652–7662. (b) Chen, Y.; Markina, N. A.; Yao, T.; Larock, R. C.
Org. Synth. 2011, 88, 377–387.
4427–4431.
B
Org. Lett., Vol. XX, No. XX, XXXX

protecting group (TES). After removal of both protecting
groups, formation of the methyl ester with TMSCl in
Table 1. Synthesis of Various N-Methyl-D-tryptophans by
Coupling between Aldehyde 11 and Iodoanilines 12aÀe
19
methanol followed by protection of the amino group
gave propargyl glycine 15 in an overall yield of 71% (3 steps).
a
2
0
Initially we used a tert-butyl ester group in glycine imine 17,
but the deprotection with TMSCl took 3 d and was accom-
panied by partial cleavage of the TES.
Scheme 3. Synthesis of Propargyl Glycine 15 by Enantioselec-
tive Propargylation of Glycine Imine 17 in the Presence of Chiral
Ammonium Salt 19
1
2
3
entry
R
R
R
12, 13
yield of 13 (%)
1
2
3
4
5
H
H
H
H
H
H
H
a
b
c
51
54
47
43
38
CO
Cl
H
2
Me
Me
H
Me
H
d
e
OMe
a
2
Reaction conditions: Pd(OAc) (13 mol %), DABCO (3 equiv),
aldehyde 11 (1 equiv), iodoaniline 12 (1.3 equiv), DMF, 100 °C, 12À20 h.
The ee-value for 13a was better than 99%.
1
4
reaction. A corresponding substrate, propargyl glycine 16,
which also should lead directly to N-methyl-D-tryptophans,
was prepared by two different routes. In route one, com-
pound 15 was synthesized from iodide 7 by the aforemen-
tioned Jackson zinc insertion protocol followed by coupl-
ing of the organozinc intermediate 8 with 1-bromo-2-
1
5
16
triethylsilylacetylene (14) (Scheme 2). After reaction
of N-Boc-alanine derivative 15 with iodomethane and
silver(I) oxide, compound 16 was obtained in 96% yield.
With propargyl glycine 16 in hand, the palladium-catalyzed
coupling with ortho-iodoanilines 12 using the Larock proto-
1
3
col gave D-abrines 21aÀe in 67À95% yield. The obtained
ee values were generally larger than 96% (Table 2). Again,
the ee-value was determined for the parent compound 21a,
indicating a high ee of 96%.
Scheme 2. Synthesis of Propargyl Glycine 16 from
Iodoalanine 7
Table 2. Synthesis of Various N-Methyl-D-tryptophans by
a
Coupling between Alkyne 16 and Iodoanilines 12aÀe
In the second route, the functionalized alkyne 15 was
prepared by enantioselective alkylation of cumyl ester
1
7
protected glycine imine 17 and propargyl bromide 18,
in the presence of phase transfer catalyst 19 (ee = 96%)
(
1
2
3
1
8
Scheme 3). Then, hydrolysis of the imine function and
entry
R
R
R
12, 21
yield of 21 (%)
1
2
3
4
5
H
H
H
H
H
H
H
a
b
c
78
67
78
95
82
cleavage of the cumyl ester was done by hydrogenolysis in
methanol, while maintaining the acid labile acetylene
CO
Cl
H
2
Me
Me
H
Me
H
d
e
(
15) Prepared according to (a) Marino, J. P.; Nguyen, H. N. J. Org.
OMe
Chem. 2002, 67, 6841–6844. (b) Dembinski, R.; Lis, T.; Szafert, S.;
Mayne, C. L.; Bartik, T.; Gladysz, J. A. J. Organomet. Chem. 1999, 578,
a
Reaction conditions: Pd(OAc)
CO (3 equiv), n-Bu NCl (1 equiv), iodoaniline 12 (1 equiv), alkyne
2
3
(5 mol %), Ph P (0.1 equiv),
2
29–246. (c) Trofimov, A.; Chernyak, N.; Gevorgyan, V. J. Am. Chem.
Soc. 2008, 130, 13538–13539.
16) Newhouse, T.; Lewis, C. A.; Baran, P. S. J. Am. Chem. Soc. 2009,
31, 6360–6361.
17) Watanabe, T.; Imaizumi, T.; Chinen, T.; Nagumo, Y.; Shibuya,
M.; Usui, T.; Kanoh, N.; Iwabuchi, Y. Org. Lett. 2010, 12, 1040–1043.
18) Respondek, T.; Cueny, E.; Kodanko, J. J. Org. Lett. 2011, 14,
50–153.
Na
2
3
4
t1 h6 a( n0 . 98 63 %e q. uiv), DMF, 110 °C, 11À16 h. The ee-value for 21a was better
(
1
(
(
(19) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.;
Martin, V. S. J. Org. Chem. 1998, 63, 3741–3744.
1
Org. Lett., Vol. XX, No. XX, XXXX
C

In summary, we have described the direct synthesis of a
variety of known and novel N-Boc-N-methyl-tryptophans
by palladium-catalyzed annulation of ortho-iodoanilines
Acknowledgment. Financial support by the NIH (grant
AI073155) and the Fonds der Chemischen Industrie is grate-
fully acknowledged. This work was carried out within the
framework of COST Action CM0804 À Chemical Biology
with Natural Products.
12 with either (R)-methyl2-((tert-butoxycarbonyl)(methyl)-
amino)-5-oxopentanoate (11) or (R)-methyl 2-((tert-butoxy-
carbonyl)(methyl)amino)-5-(triethylsilyl)pent-4-ynoate (16).
The yields for the annulation step were generally higher using
the Larock variant. These abrines should be useful for
incorporation into peptides and depsipeptides.
Supporting Information Available. Experimental details
1
13
and H and C NMR spectra for all new compounds. This
material is available freeof chargevia the Internetat http://
pubs.acs.org.
(
20) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-g. Org.
Lett. 2002, 4, 4245–4248.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX