Synthesis of the celogentin C right-hand ring

Article abstract of DOI:10.1021/ol060016f

Synthesis of the cyclic tetrapeptide comprising the right-hand ring of celogentin C, a potent inhibitor of tubulin polymerization, has been accomplished. A mild oxidative coupling reaction permitted construction of the indole-imidazole linkage via a conve

Full text of DOI:10.1021/ol060016f

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1165-1168
Synthesis of the Celogentin C
Right-Hand Ring
Liwen He, Liping Yang, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602
scastle@chem.byu.edu
Received January 3, 2006
ABSTRACT
Synthesis of the cyclic tetrapeptide comprising the right-hand ring of celogentin C, a potent inhibitor of tubulin polymerization, has been
accomplished. A mild oxidative coupling reaction permitted construction of the indole imidazole linkage via a convergent union of two fully
functionalized dipeptides. A high-yielding macrolactamization and subsequent deprotection of the N-terminus furnished the target compound.
−
Celogentin C (1, Figure 1) is a bicyclic octapeptide isolated
by Kobayashi from the seeds of Celosia argentea.1 It is a
member of a growing family of structurally similar bicyclic
peptides including moroidin2 and celogentins A-J3 as well
as the related monocyclic peptides celogentin K4 and
stephanotic acid.5 Many of these natural products inhibit the
polymerization of tubulin,6 with 1 ranking as the most potent
agent of this class of compounds. The unusual architecture
of 1 is derived from two cross-links, one joining the leucine
â-carbon with the indole C-6 of tryptophan, and the other
connecting the tryptophan indole C-2 with the imidazole N-1
of histidine. Despite the combination of complex structural
features with useful biological activity, published synthetic
studies of the celogentin family are scarce. Moody has
disclosed syntheses of the moroidin right-hand ring7 and the
central tryptophan residue of stephanotic acid.8 Our efforts
toward the construction of 1 commenced with the asymmetric
preparation of a suitably functionalized tryptophan subunit.9
Herein, we report the synthesis of the right-hand ring of 1
which relies on a mild intermolecular oxidative coupling of
(1) Kobayashi, J.; Suzuki, H.; Shimbo, K.; Takeya, K.; Morita, H. J.
Org. Chem. 2001, 66, 6626.
(2) (a) Leung, T.-W. C.; Williams, D. H.; Barna, J. C. J.; Foti, S.;
Oelrichs, P. B. Tetrahedron 1986, 42, 3333. (b) Kahn, S. D.; Booth, P. M.;
Waltho, J. P.; Williams, D. H. J. Org. Chem. 1989, 54, 1901.
(3) Celogentins A-C: ref 1. Celogentins D-J: Suzuki, H.; Morita, H.;
Iwasaki, S.; Kobayashi, J. Tetrahedron 2003, 59, 5307.
(4) Suzuki, H.; Morita, H.; Shiro, M.; Kobayashi, J. Tetrahedron 2004,
60, 2489.
(5) Yoshikawa, K.; Tao, S.; Arihara, S. J. Nat. Prod. 2000, 63, 540.
(6) Morita, H.; Shimbo, K.; Shigemori, H.; Kobayashi, J. Bioorg. Med.
Chem. Lett. 2000, 10, 469; see also refs 1 and 3.
(7) (a) Harrison, J. R.; Moody, C. J. Tetrahedron Lett. 2003, 44, 5189.
(b) Comber, M. F.; Moody, C. J. Synthesis 1992, 731.
(8) Bentley, D. J.; Moody, C. J. Org. Biomol. Chem. 2004, 2, 3545.
(9) Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
Figure 1. Celogentin C.
10.1021/ol060016f CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/24/2006

two fully functionalized dipeptides to form the indole-
imidazole linkage. A subsequent high-yielding macro-
lactamization creates the 17-membered ring.
The oxidative coupling process is illustrated in conceptual
fashion in Figure 2. We postulated that exposure of a
reaction. Accordingly, N-phthaloyltryptophan (2)13 was
joined with proline benzyl ester under standard peptide-
coupling conditions. With dipeptide 3 in hand, we com-
menced our exploration of its oxidative coupling with
imidazole.
The results of these investigations of the oxidative coupling
process are collected in Table 1. Of the oxidants examined,
Table 1. Oxidative Coupling of 3 and Imidazole
Figure 2. Proposed oxidative coupling process.
entry
oxidanta
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
8
NCS
NBS
NIS
t-BuOCl
NCS
NCS
NCS
NCS
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
CH2Cl2
EtOAc
CH2Cl2
-78
-78
-78
-78
0
0
rt
rt
54
37
smb
smb
73
72
69
77
tryptophan derivative to a suitable electrophile would result
in formation of a transient iminium ion. Trapping of this
intermediate by the histidine imidazole and subsequent
elimination would generate the desired link between the two
heterocycles. Similar reactions have been performed by
Booker-Milburn with alcohol nucleophiles10 and by Bergman
with anilines,11 phenols, and thiophenols.12 However, two
potential problems concerned us. First, we questioned
whether imidazole could function as a competent nucleophile
in this process. Second, we feared that the ability of the
product to react with the electrophilic reagent could com-
plicate matters. Accordingly, we decided to examine the
coupling of a tryptophan-containing dipeptide with imidazole
prior to employing more complex histidine-containing nu-
cleophiles.
a 1 equiv of oxidant was used in each reaction, and 1,4-dimethylpiperazine
was used as base. b Complete recovery of starting material.
N-chlorosuccinimide proved the most effective (entry 1 vs
entries 2-4). Use of dimethyldioxirane14 afforded the
oxindole derived from 3 presumably due to rearrangement
of the intermediate epoxide (data not shown). Screening of
solvents and reaction temperatures established the conditions
given in entry 8 (NCS, CH2Cl2, rt) as optimal for the
production of 4. Although EtOAc was also a viable solvent,
others examined were less effective.15 In all reactions,
recovered 3 accounted for the balance of the material.
Attempts to drive the reaction to completion by using excess
NCS were unsuccessful; lower yields of 4 were obtained,
presumably due to the ability of 4 to react with the oxidant.
Finally, we observed that very pure samples of the starting
dipeptide 3 were essential to obtaining reproducible results.
We speculate that impurities present in the starting material
may react with the sensitive chloroindolenine intermediate,
thereby reducing the yield of 4.
Synthesis of the requisite dipeptide 3 was straightforward
and is depicted in Scheme 1. We elected to protect the
Scheme 1. Synthesis of Dipeptide 3
With optimal oxidative coupling conditions established,
we next prepared the histidine-containing dipeptide necessary
for synthesis of the celogentin C right-hand ring. Coupling
of NR-Cbz-NG-Pbf-arginine (5)16 with histidine tert-butyl ester
N-terminus of tryptophan as a phthalimide due to concerns
that the more commonly employed carbamate protecting
groups might not prevent the nitrogen atom from engaging
the chloroindolenine intermediate of the oxidative coupling
(13) Casimir, J. R.; Guichard, G.; Briand, J.-P. J. Org. Chem. 2002, 67,
3764.
(14) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964.
(15) Yields for reactions with other solvents: acetone, 52%; THF, 45%;
Et2O, <10%; CH3CN, <10%; DMF, no product observed.
(16) Carpino, L. A.; Shroff, H.; Triolo, S. A.; Mansour, E.-S. M. E.;
Wenschuh, H.; Albericio, F. Tetrahedron Lett. 1993, 34, 7829.
(10) Booker-Milburn, K. I.; Fedouloff, M.; Paknoham, S. J.; Strachan,
J. B.; Melville, J. L.; Voyle, M. Tetrahedron Lett. 2000, 41, 4657.
(11) Bergman, J.; Engqvist, R.; Stålhandske, C.; Wallberg, H. Tetra-
hedron 2003, 59, 1033.
(12) Engqvist, R.; Bergman, J. Tetrahedron 2003, 59, 9649.
1166
Org. Lett., Vol. 8, No. 6, 2006

(6)17 under standard conditions provided dipeptide 7 (Scheme
2). We chose the 2,2,4,6,7-pentamethyldihydrobenzofuran-
5-sulfonyl (Pbf) moiety as our guanidine protecting group
due to reports that it can be cleanly and rapidly removed
under acidic conditions from tryptophan-containing pep-
tides.16
Scheme 4. Completion of Celogentin C Right-Hand Ring
Scheme 2. Synthesis of Dipeptide 7
plete scission of the N-Cbz moiety, even when high pressures
of H2 (100 psi) were used. Then, exposure of a dilute solution
of 9 to HBTU, HOBt, and i-Pr2NEt afforded smooth
macrolactamization, as cyclic peptide 10 was isolated in 96%
yield. HATU was as effective as HBTU in mediating
cyclization; however, we chose to utilize the less expensive
reagent.18 Reactions employing EDCI‚HCl as peptide cou-
pling agent were slightly less effective (86% yield).
In contrast to all acyclic proline-containing intermediates
which existed as mixtures of conformational isomers in
solution, cyclic tetrapeptide 10 adopted a single detectable
conformation in DMSO-d6. Interestingly, the free amine 11,
generated by hydrazinolysis of 10,19 adopted two distinct
conformations in DMSO-d6 (1.4:1 ratio). Apparently, the
bulky phthalimide moiety locks the macrocycle of 10 into a
single orientation, whereas the absence of substitution on
the amine in 11 allows slow rotation about either the tertiary
amide bond or the indole-imidazole axis to occur. In the
natural product itself, such rotation is precluded by the
presence of the left-hand ring, since 1 exists as a single
conformer in solution.1
When dipeptides 3 and 7 were subjected to the previously
developed oxidative coupling conditions, the desired product
8 containing the required indole-imidazole linkage emerged
in 58% yield (Scheme 3). As before, the reaction could not
be driven to completion, presumably due to the propensity
of 8 to react with NCS. However, both starting materials
could be easily recovered, as 3, 7, and 8 were readily
separable by flash chromatography.
Scheme 3. Oxidative Coupling of Dipeptides 3 and 7
The ROESY spectrum of 10 exhibits correlations between
indole NH and imidazole H-2 as well as Trp â-H and
imidazole H-5. These and other diagnostic through-space
correlations are shown in Figure 3 superimposed on an MM2-
minimized model of 10. The spectroscopic data are consistent
with the minimized structure. Interestingly, the NOESY
spectrum of 1 shows the opposite correlations (i.e., indole
NH/imidazole H-5 and Trp â-H/imidazole H-2),1 indicating
that the configuration about the indole-imidazole bi(hetero)-
aryl axis is reversed for the two compounds. Apparently,
the presence of the left-hand macrocycle in 1 causes the
indole moiety to change its orientation relative to the
Intermediate 8 was successfully elaborated into the right-
hand ring of celogentin C as portrayed in Scheme 4. Transfer
hydrogenation resulted in cleavage of both the benzyl ester
and carbamate groups, providing macrocyclization substrate
9 in high yield. Notably, attempts to employ standard
catalytic hydrogenation conditions were plagued by incom-
(17) Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J. Org. Chem. 1994,
59, 3216. The tert-butylating reagent used herein, N,N-diisopropyl-O-tert-
butylisourea, is difficult to prepare due to the requirement for strictly
anhydrous t-BuOH. Accordingly, we developed a more convenient prepara-
tion of 6 which is given in Supporting Information.
(18) For a review of peptide coupling reagents, see: Albericio, F.;
Chinchilla, R.; Dodsworth, D. J.; Na´jera, C. Org. Prep. Proced. Int. 2001,
33, 203.
(19) Sasaki, T.; Minamoto, K.; Itoh, H. J. Org. Chem. 1978, 43, 2320.
Org. Lett., Vol. 8, No. 6, 2006
1167

conditions employed in the oxidative coupling reaction
permitted us to form the crucial indole-imidazole linkage
by joining two highly functionalized dipeptides.20 Addition-
ally, our approach does not require activation of the indole
C-2 with a halogen or other substituent, thereby increasing
the efficiency of the route. Application of this process to
the total synthesis of 1 itself is ongoing and will be reported
in due course.
Acknowledgment. We thank Brigham Young University
(startup funds to S.L.C., Cancer Research Center Fellowship
to L.Y.) and the National Institutes of Health (GM70483)
for support of this work. We also thank Professor Paul A.
Wender of Stanford University for helpful discussions.
Supporting Information Available: Details of the syn-
thesis of 6; experimental procedures, characterization data,
and NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 3. Selected ROESY correlations of 10 (Pbf group and some
hydrogens removed for clarity).
imidazole. Our observations are supported by molecular
modeling, as an MM2-minimized representation of 1 pos-
sesses the opposite configuration about the bi(hetero)aryl axis
when compared to 10 due to a change in the position of the
indole.
OL060016F
(20) The SNAr-type reaction employed by Moody to fashion the
analogous linkage in the synthesis of the moroidin right-hand ring (see ref
7a) required both strong base (NaHMDS) and heat. Consequently, this
transformation, although high-yielding (89%), was performed with relatively
simple compounds that were later elaborated into amino acids and peptides.
In conclusion, we have constructed the right-hand ring of
the antimitotic bicyclic peptide celogentin C. The mild
1168
Org. Lett., Vol. 8, No. 6, 2006