Annulated diketopiperazines from dipeptides or schoellkopf reagents via tandem cyclization-intramolecular N-arylation

Article abstract of DOI:10.1021/ol100663y

Figure presented Facile CuI-mediated N-arylation of diketopiperazine using the Fukuyama modification of the Ullmann-Goldberg reaction can be exploited in new approaches to enantiopure polycyclic diketopiperazines from easily assembled dipeptides or functi

Full text of DOI:10.1021/ol100663y

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2162-2165
Annulated Diketopiperazines from
Dipeptides or Scho¨llkopf Reagents via
Tandem Cyclization-Intramolecular
N-Arylation
Hwan Jung Lim, Judith C. Gallucci, and T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity, 100 W. 18th AVenue,
Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received March 25, 2010
ABSTRACT
Facile CuI-mediated N-arylation of diketopiperazine using the Fukuyama modification of the Ullmann-Goldberg reaction can be exploited in
new approaches to enantiopure polycyclic diketopiperazines from easily assembled dipeptides or functionalized Scho¨llkopf reagents.
Several molecules containing a 2,5-diketopiperazine (1, DKP)
moiety show promising biological activities which are helpful
in treating human diseases (e.g., 2, 3; Figure 1).1 However,
used a stepwise synthesis starting from indole 2-carboxylic
acid derivatives.2 Our studies in the area had its origin in an
approach to lyngbyatoxin A, a potent PKC inhibitor, in which
we planned to use a biosynthesis-inspired3 N-arylation to
construct the nine-membered lactam (Figure 2). While
investigating the properties of a dipeptide precursor (4, X )
Y ) Br) for this intramolecular N-arylation, we have
uncovered a number of potentially useful transformations that
are relevant to the synthesis of functionalized diketopipera-
zines, and here we report the details of these investigations.
Our studies started with the assembly of the indolyldipep-
tide 13b (Scheme 1).4 The starting point for the synthesis is
a one-step preparation of 4,7-dibromoindole 5 via the Bartoli
protocol.5 Reaction of 5 with POCl3 and DMF gives the
Figure 1. Diketopiperazines.
there is no general method for the synthesis of enantiopure
pyrazino[1,2-a]indole-1,4-diones (2), which have potent
immunosuppressive and antimicrobial activities. Reported
nonstereoselective methods for this important pharmacophore
(2) (a) Vigushin, D. M.; Brooke, G.; Willows, D.; Coombes, R. C.;
Moody, C. J. Bioorg. Med. Chem. Lett. 2003, 13, 3661. For a Pd-catalyzed
cyclization of an N-allyl derivative derived from indole-2-carboxylic acid,
see: (b) Abbiati, G.; Beccalli, E.; Broggini, G.; Martinelli, M.; Paladino,
G. Synlett 2006, 73. (c) Attia, M. I.; Julius, J.; Witt-Enderby, P. A.; Zlotos,
D. P. Tetrahedron 2007, 63, 754.
(1) For recent reviews on the synthesis and biological activities of DKP,
see: (a) Martins, M. B.; Carvalho, I. Tetrahedron 2007, 63, 9923. (b)
Dinsmore, C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297.
(3) Edwards, D. J.; Gerwick, W. H. J. Am. Chem. Soc. 2004, 126, 11432.
(4) See Supporting Information for experimental details and full
characterization data for all new compounds including CIF for 14.
10.1021/ol100663y  2010 American Chemical Society
Published on Web 04/13/2010

tography. Installation of the additional chiral center in 12
turned out to be more challenging than we anticipated as
even the best Rh catalysts give only modest diastereoselec-
tivity in the asymmetric hydrogenation reaction. Selected
results of Rh-catalyzed hydrogenation of 12 with various
catalysts are reported in Table 1 in the Supporting Informa-
tion.4 Although various DIOP and bis-2,5-diphenylphosphi-
nohexane ligands8a give excellent conversion at 90 psi of
hydrogen in deoxygenated methanolic solution, the best result
8b
is obtained with [Rh(Et-DuPhos)(COD)]+OTf- as the
precatalyst, which yields 8.5:1.0 dr of 13a, which upon
deprotection gave 13b.
Figure 2
intramolecular N-arylation.
. Lyngbyatoxin via asymmetric hydrovinylation and
With the appropriately protected substrates 13b and 13c
in hand, we first examined various intramolecular amination
procedures to prepare the nine-membered lactam. Our initial
attempts focused on Pd-catalyzed N-arylation reactions9 of
13c, under conditions remniscent of Buchwald’s synthesis
of dehydrobufotenine.10 These experiments (Table 2, Sup-
porting Information)4 were uniformly unsuccessful and lead
to no discernible products. Next we turned our attention to
the Fukuyama modification9f of the Ullmann-Goldberg
reaction, which he has used very effectively to prepare highly
functionalized nitrogen heterocycles. Studies4 of various
substrates quickly revealed that the substrate 13b, with both
amines deprotected, is compatible with the standard condi-
tions under which these cyclization reactions are run.
However, none of the expected tricyclic compound (15b) is
formed under a variety of conditions. Instead, a diketopip-
erazine derivative 14 is formed in acceptable yield (eq 1).
Scheme 1. Synthesis of Indolylpeptide for Cyclization
The structure of the tetracyclic diketopiperazine 14 has been
unambiguously established by determination of the solid-state
structure of a crystalline hydrate. Several features of this reaction
are worthy of note: (i) under these conditions, only the 4-Br
group undergoes displacement, leaving behind the 7-Br un-
touched; (ii) in the product isolated, there is no epimerization
carboxaldehyde 6, which after Boc-protection of the nitrogen
is converted into the dehydroamino acid derivative 12 via a
modified Horner-Emmons reaction using the phosphonate
11.6 Schmidt’s phosphonate 11 was prepared by Rh-catalyzed
carbene insertion into a N-H bond of the amide 9.7 The
Horner-Emmons reaction of the aldehyde 7 with the
phosphonate 11 under the prescribed procedure gives 71%
of the pure (Z)-dehydrodipeptide 12 after column chroma-
(9) For papers by leading researchers in the area, see: (a) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046. (b) Yang, B. H.; Buchwald, S. L.
J. Organomet. Chem. 1999, 576, 125. For key references of Cu-mediated
aminations, see: (c) Klapars, A.; Huang, X; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421. (d) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359. (e) Tye, J. W.; Weng, Z.; Johns,
A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 9971.
(f) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.; Fukuyama,
T. Tetrahedron 2008, 64, 11230. (g) Ma, D.; Cai, Q. Acc. Chem. Res. 2008,
41, 1450. (h) Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108,
3054. (i) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. For an especially
valuable review that highlights the historical aspects of this crowded area
and the relative synthetic advantages of the various methods, see: (j) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(5) (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129. (b) Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J. J.
Org. Chem. 2003, 68, 9835.
(6) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487.
(7) Buck, R. T.; Clarke, P. A.; Coe, D. M.; Drysdale, M. J.; Ferris, L.;
Haigh, D.; Moody, C. J.; Pearson, N. D.; Swann, E. Chem.sEur. J. 2000,
6, 2160.
(10) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028.
(11) (a) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett
2002, 231. (b) Okano, K.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc.
2006, 128, 7136. (c) Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama,
T. J. Am. Chem. Soc. 2003, 125, 6630.
(8) (a) Yan, Y.; RajanBabu, T. V. Org. Lett. 2000, 2, 4137. (b) DuPhos
ligands: Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125.
Org. Lett., Vol. 12, No. 9, 2010
2163

at the two chiral centers, which is quite different from such a
complication seen in intermolecular N-arylation of a diketopip-
erazine under the Buchwald conditions (CuI, trans-1,2-diami-
nocyclohexane, 110 °C, dioxane).12
Scheme 3
.
Synthesis of 2-(2-Bromobenzyl)diketopiperazine
Precursors
The tetracyclic diketopiperazine, 14, while it does not fill
the need for our projected synthesis of lyngbyatoxin,
nonetheless raises interesting questions about further utility
of these compounds and the chemistry of its formation. For
example, these compounds can be thought of as conforma-
tionally rigid congeners of indolactams, a class of compounds
with significant biological activities.13 Likewise, this chem-
istry, especially the tandem formation of a diketopiperazine
and the N-arylation (not necessarily in that order) could
provide access to novel structures from readily available
precursors such as dipeptides. In addition, this route might
facilitate the synthesis of a class of compounds known as
mycenarubins,14 which carry an epimerizable center next to
the amide involved in the arylation.
Plausible routes to the formation of 14 from 13b are shown
in Scheme 2. It is conceivable that the expected medium
The dipeptide substrates were prepared (Scheme 3) fol-
lowing the scheme developed earlier for the synthesis of 13b
(Scheme 1). In this instance, for the hydrogenation of the
dehydrodipeptide 18, our D-glucose-derived 1,2-bis-dia-
rylphosphinite-Rh complexes16 (Table 3 in Supporting
Information) gave the best results (dr ) 6.8:1.0) for 19.
Scheme 2. Formation of 14 from 13b
Scheme 4
.
Synthesis of 2-(2-Halobenzyl)dipeptides via a
Scho¨llkoff Reagent
size ring formation (Figure 2) is kinetically unfavorable, and
a more facile six-membered ring annulation (path a, Scheme
2) followed by cyclocondensation (path b) to give the DKP
nucleus ensues. Alternatively, the dipeptide undergoes a base-
mediated cyclization to a diketopiperazine (path c) followed
by an intramolecular N-arylation (path d). If paths c/d are
indeed followed, this might suggest that diketopiperazines
prepared in situ from dipeptides could serve as broadly useful
partners in N-arylation reactions.15 To explore this possibility,
we decided to examine the cyclization of two sets of simpler
substrates, one derived from dipeptides, where we can
explore the tandem reactions, and another, preformed dike-
topiperazines, where the direct N-arylation of these substrates
can be studied.
In a different approach, the desired dipeptides were also
prepared via the Scho¨llkopf reagents (Scheme 4). The ortho-
halophenylalanine derivatives 23a and 23b are very useful
intermediates that could be used for the synthesis of a wide
variety of dipeptide derivatives in enantiomerically pure
(12) Beghyn, T.; Hounsou, C.; Deprez, B. P. Bioorg. Med. Chem. Lett.
2007, 17, 789.
(13) Kozikowski, A. P.; Shum, P. W.; Basu, A.; Lazo, J. S. J. Med.
Chem. 1991, 34, 2420, and references cited therein.
(14) Peters, S.; Spiteller, P. Eur. J. Org. Chem. 2007, 1571.
(15) For the use of diketopiperazines in intramolecular cyclization of
2-iodotryptophans, see: Coste, A.; Toumi, M.; Wright, K.; Razafimahaléo,
V.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841.
(16) (a) RajanBabu, T. V.; Ayers, T. A.; Casalnuovo, A. L. J. Am. Chem.
Soc. 1994, 116, 4101. (b) RajanBabu, T. V.; Ayers, T. A.; Halliday, G. A.;
You, K. K.; Calabrese, J. C. J. Org. Chem. 1997, 62, 6012.
2164
Org. Lett., Vol. 12, No. 9, 2010

form. Examples of Phe-Val (25a, 25b) and Phe-Pro (26b)
derivatives are illustrative. The dipeptides 19, 20, 25b, and
26b were subjected to the Cu-mediated cyclization reactions
(Scheme 5), and the results are shown in Table 1. The Boc-
nitrogen is a significantly better nucleophile in N-arylation
reactions. These observations are consistent with the facile
cyclization of the indolyldipeptide 13b (eq 1, Scheme 2),
which prompted us to initiate this line of research.
The results described in the previous section raises the
possibility that partially hydrolyzed Scho¨llkopf reagents could
be used directly (without going through an intermediate
amino acid) for the synthesis of diketopiperazine-annulated
heterocycles, especially the 2,5-trans derivatives. An example
of this seldom used strategy17 is shown in Scheme 6. The
Scheme 5. Tandem Cycliztion and Intramolecular N-Arylation
for the Formation of Diketopiperazines from Dipeptides
Scheme 6. Cu(I)-Catalyzed Annulation of Diketopiperazines
Table 1. Cu-Mediated Tandem Cyclization/N-Arylation
no. sm
conditionsa
product yieldc(%)
1
2
19
19
CuI (1 equiv)
no cyclized product
(19 recovered)
CsOAc (2.5 equiv) no cyclized product
onlyb
(19 recovered, 23% racemization)
3
4
5
6
7
20
20
CuI (1 equiv)
CuI (0.1 equiv)
27/28 (59, 18)
27/28 (20, 69)
27/28 (77, 8)
27/28 (32, 61)
29/30 (48, 12)
25b CuI (1 equiv)
25b CuI (0.1 equiv)
26b CuI (1 equiv)
ortho-halobenzyl derivatives 22a and 22b, readily prepared
from Scho¨llkopf reagents (Scheme 4), are partially hydolyzed
to the diketopiperazines 31a and 31b. Intramolecular N-
arylation of these substrates gives excellent yields of the
annulated products 32 and 33.
a Unless otherwise mentioned, all reactions used 2.5 equiv of CsOAc
and heated to 90 °C for 12 h under N2 in DMSO as a solvent. b Reaction
temperature was 110 °C without CuI. c Isolated yields, and the extent of
1
isomerization was determined by H NMR.
The iodo derivative 31b is an especially good substrate
showing no sign of epimerization under the stoichiometric
CuI-mediated reactions. For characterization purposes, we
converted 32 into ent-28, a compound that was prepared by
the asymmetric hydrogenation/tandem cyclization/N-arylation
route (Schemes 4 and 5).
In summary, in this work, we demonstrate that the facile
CuI-mediated N-arylation of diketopiperazine can be ex-
ploited in new approaches to enantiopure bicyclic diketopip-
erazines from easily assembled dipeptides or functionalized
Scho¨llkopf reagents.
protected substrate 19 under a variety of conditions does not
undergo any cyclization (entries 1 and 2). With CsOAc alone,
substantial isomerization of the starting material is observed
(entry 2). Substrates in which both nitrogens of the dipeptide
are free of any protecting group undergo the tandem
cyclization/N-arylation (entries 3-7). The extent of epimer-
ization seems to depend on the relative rates of the cyclization
and epimerization. Thus, the arylbromide substrate 20 with
a stoichiometric amount of CuI gives 59% of the diketopip-
erazine (27) with up to 18% isomerization (entry 3), while
the same reaction under catalytic conditions (10 mol % of
CuI) yields the isomerized product 28 as the major compo-
nent (entry 4). Best results are seen by treating 25b with 1
equiv of CuI and 2.5 equiv of CsOAc in DMSO at 90 °C,
conditions under which 77% yield of the cyclic product 27
is obtained. Use of catalytic amounts of CuI leads to
substantial epimerization to the more stable trans-2,5-dialkyl
derivative (entry 6). The tandem cyclization-N-arylation
appears to be quite general, and even a proline-derived
dipeptide (26b) undergoes the reaction (entry 7). These
results along with absence of cyclization in the N-protected
derivative 19 (entry 1) suggest that the diketopiperazine
Acknowledgment. This work was supported by a grant
from NIH (R01 GM075107).
Supporting Information Available: Experimental pro-
cedures for the synthesis of all new compounds and their
full characterization including the CIF for 14. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL100663Y
(17) For another notable example, see: Andrei, M.; Ro¨mming, C.;
Undheim, K. Tetrahedron: Asymmetry 2004, 15, 1359.
Org. Lett., Vol. 12, No. 9, 2010
2165