Total synthesis of luzopeptin C

Article abstract of DOI:10.1016/S0040-4039(01)00080-6

The synthesis of luzopeptin C has been accomplished by self-assembly of the macrocycle via activation of a pentapeptide monomer. The present work underscores the generality of the spontaneous macrocyclization approach to the peptins, a strategy introduced

Full text of DOI:10.1016/S0040-4039(01)00080-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1907–1909
Total synthesis of luzopeptin C
Delphine Valognes,a Philippe Belmont,a Ning Xib and Marco A. Ciufolinia,b,
*
aLaboratoire de Synthe`se et Me´thodologie Organiques (LSMO), UMR CNRS 5078,
Universite´ Claude Bernard Lyon 1 et Ecole Supe´rieure de Chimie, Physique, Electronique de Lyon, 43,
Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
bDepartment of Chemistry, Rice University, 6100 Main Street, Houston, TX 77005, USA
Received 11 January 2001; accepted 12 January 2001
Abstract—The synthesis of luzopeptin C has been accomplished by self-assembly of the macrocycle via activation of a
pentapeptide monomer. The present work underscores the generality of the spontaneous macrocyclization approach to the
peptins, a strategy introduced by us in connection with the synthesis of luzopeptin E2. © 2001 Elsevier Science Ltd. All rights
reserved.
Luzopeptins1 and quinoxapeptins2 constitute what may
be termed the ‘peptin’ family of natural products. These
substances display extremely interesting biological activ-
ities. For instance, luzopeptin C and quinoxa-peptins
are potent inhibitors of HIV replication at non-cyto-
toxic levels in human T-cells in vitro,2,3 while luzopeptin
A may be of interest as an antitumor agent, due to its
1000-fold greater cytotoxicity relative to mitomycin C.1
Peptins exhibit a largely invariant depsipeptide macro-
cycle composed of two identical subunits and containing
piperazic acid (piz),4 N-methyl-3-hydroxyvaline (mhv),
The first reports detailing synthetic studies toward
luzopeptins date from the mid-1980s; yet, the extreme
difficulties associated with the endeavor have been con-
quered only very recently. The first syntheses of 1–3
and of quinoxapeptins were announced in 1999 by
Boger,6 who also explored various aspects of the bioac-
tivity of the peptins,7 and who has recently disclosed
full details of this work.8 Our own involvement in the
peptin field has generated a number of principles for
the formulation of a synthetic plan;9 in particular, the
establishment of methodology for the formation of a
D
-serine, sarcosine and glycine. The structures of four
problematic piz–D
-serine dipeptide.10 These efforts have
luzopeptins have been firmly established and are shown
in Fig. 1.5 Quinoxapeptins differ from luzopeptins for
the nature of the heteroaroyl ‘wings’ bound to the serine
NH2 groups and of the acyloxy substituents Z/Z% on the
piz units.2
recently culminated in the total synthesis of 4.11 A key
aspect of this work is an especially concise solution to
the problem of macrocycle assembly. Thus, it was
found that the 32-membered ring of luzopeptin E2
self-assembles upon carboxy terminus activation of a
MeO
Y
Z'
O
O
Me
N
H
N
H
OH
Luzopeptin
A
1
2
3
4
X, Y = 1/4 bond; Z = Z' = OAc
X, Y = 1/4 bond; Z = OH, Z' = OAc
X, Y = 1/4 bond; Z = Z' = OH
X = Y = Z = Z' = H
X
H
N
N
N
N
N
Me
B
H
O
O
C
O
O
N
O
OH
H
E2
H
OH
O
O
O
N
O
H
O
Me
N
O
Z
N
H
N
N
H
N X
HO
H
Me
O
Y
OMe
Figure 1.
Keywords: aminoacids; antiviral compounds; HIV; luzopeptins; macrocyles.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00080-6

1908
D. Valognes et al. / Tetrahedron Letters 42 (2001) 1907–1909
pentapeptide of the type 12. However, the piz compo-
nent of 4 lacks the oxygen functionality at the b-posi-
tion of the carboxy unit, and it is thus considerably
sturdier than the analogous component of luzopeptins
A–C and quinoxapeptins. Earlier work from our group
had raised some doubts concerning the applicability of
the strategy devised for luzopeptin E2 to the more
complex and sensitive C series of peptins. In particular,
we had concluded that b-elimination of the OH group
in the piz unit may complicate base-promoted oxa-
zolone cleavage in substrates of the type 8,10a which are
obligatory intermediates toward the ultimate goals. We
have now elaborated conditions suitable for the con-
duct of these operations in the oxygenated series of
substrates, and we have verified that macrocyclodimer-
ization of 12 itself is possible. In this Letter, we wish to
describe the total synthesis of luzopeptin C.
Oxazolone cleavage in system 8 may be conducted
without untoward consequences if the OH group of the
piz unit is protected as a TBS ether (Scheme 1).12
Accordingly, standard methods were employed to
advance the previously described 6 to intermediate 8,
which upon reaction with Cs2CO3 in MeOH suffered
not only release of the oxazolone ring, but also transes-
terification to methyl ester 9.13 Peptides incorporating
mhv are sensitive to the basic conditions required for
methyl ester cleavage. Prior to the union of fragment 9
with tripeptide acid 11,9e the methyl ester was therefore
exchanged with a crotyl ester, which may be released at
TBSO
AcO
HO
TBS–O
H
N
H
N
H
N
H
N
COOMe
COOiBu
O
COOiBu
O
COOiBu
b, c
a
d
e, f
O
H
O
H
N
N
N
N
H
N Ac
H
NH
HO
NHBOC
N BOC
6
7
8
O
O
O
9
OTBS
O
O
O
O-Crotyl
N
N
H
O
TBSO
O
H
BOCHN
O
O
Me
O
H
H
O
HOOC
N
g
N
+
O
12
N
O
H
O
Me
N
N
O
Me N3
10
HO
N
N3
OH
NHBOC
11
HO
H
Me
O
Scheme 1. (a) N2H4·H2O, MeCN, rt, 4 h, 99%; (b) TBS-Cl, imidazole, DMF, 16 h, 70%; (c) BOC2O, Et3N, DMAP, CH2Cl2, 95%;
(d) 10% w/w Cs2CO3, MeOH, 6 h; (e) LiOH, aq. THF, 2 h; (f) crotyl-Br, Et3N, Me2CO, 24 h, 65% d–f; (g) DCC (3 equiv.),
DMAP (2 equiv.), 0° to rt, 16 h, 60%.
OTBS
OTBS
H
N
O
Me
N
H
OH
H
H
O
N
N
O
N
N
Me
N
O
H
O
BOC–HN
O
O
BOCHN
H
HN
O
O
N
O
H
d - e
a - c
O
Me
Me
O
O
O
O
H
N
+
12
Me
N
O
NH–BOC
H
N
N
Me
N
H
N
HO
H
O
14
O
13
O
TBSO
OH
N
MeO
OTBS
H
N
O
Me
H
OH
f
N
N
3
N
N
Me
H
N
H
O
O
O
O
O
N
O
OH
H
H
OH
O
O
O
O
O
H
Me
N
H
N
N
15
N
N
H
N
HO
H
Me
O
TBSO
OMe
Scheme 2. (a) Cat. Pd(PPh3)4, dimedone, THF, rt, 5 h; (b) PPh3, H2O, THF, rt, 18 h; (c) EDCI (4 equiv.), HOAt (4 equiv.),
CH2Cl2, 0°C to rt, 16 h, 26% of 14, 9% of 13 over three steps (a–c); (d) TFA, CH2Cl2, 30 min; (e) 3-hydroxy-6-methoxyquinaldic
acid, EDCI, HOBt, DMF, NaHCO3, rt, 12 h, 55% d–e; (f) Py-HF, CH2Cl2, rt, 12% after extensive purification.

D. Valognes et al. / Tetrahedron Letters 42 (2001) 1907–1909
1909
an opportune later stage of the synthesis under neutral
conditions (cat. Pd(0)).14 The reasons for our choice of
a crotyl, rather than an allyl, ester, have been addressed
elsewhere.11 Esterification6 of 10 with free acid 11
afforded pentapeptide 12: a protected monomeric pre-
cursor to the peptin macrocycle.
ences cited therein; Luzopeptin E2: (c) Urbanus, H. M.
(Bristol-Myers Co.) Netherlands Pat. NL-T 84 00 237,
1984 [Chem. Abstr. 1985, 102, 22795q].
2. Lingham, R. B.; Hsu, A. H. M.; O’Brien, J. A.; Sigmund,
J. M.; Sanchez, M.; Gagliardi, M. M.; Heimbuch, B. K.;
Genilloud, O.; Martin, I.; Diez, M. T.; Firsch, C. F.;
Zink, D. L.; Liesch, J. M.; Koch, G. E.; Gartner, S. E.;
Garrity, G. M.; Tsou, N. N.; Salituro, G. M. J. Antibiot.
1996, 49, 253.
3. (a) Inouye, Y.; Take, Y.; Nakamura, S. J. Antibiot. 1987,
40, 100; (b) Take, Y.; Inouye, Y.; Nakamura, S.;
Allaudeen, H. S.; Kubo, A. J. Antibiot. 1989, 44, 107.
4. Review: Ciufolini, M. A.; Xi, N. Chem. Soc. Rev. 1998,
437.
5. The structures of luzopeptins D and E1 remain unknown,
or at least they are not in the public domain.
6. (a) Luzopeptins: Boger, D. L.; Lederboer, M. W.; Kume,
M. J. Am. Chem. Soc. 1999, 121, 1098; (b)
Quinoxapeptins: Boger, D. L.; Lederboer, M. W.; Kume,
M.; Jin, Q. Angew. Chem., Int. Ed. Engl. 1999, 38, 2424.
7. (a) Boger, D. L.; Chen, J. H.; Saionz, K. W.; Jin, Q.
Bioorg. Med. Chem. 1998, 6, 85; (b) Boger, D. L.; Saionz,
K. W. Bioorg. Med. Chem. 1999, 7, 315.
Carboxy and amino termini in 12 were deblocked to
yield the corresponding free aminoacid, an extremely
polar substance, which was neither purified15 nor exten-
sively characterized. Rather, it was immediately sub-
jected to the macrocyclization conditions devised for
luzopeptin E2 (70 mg/mL in CH2Cl2, EDCI, HOAt),
whereupon the desired macrocyclic dimer 14 emerged in
26% chromatographed yield, together with undesired
cyclic monomer 13 (ca. 9%) (Scheme 2). Unreacted
starting aminoacid (10–15%) and high molecular mass
byproducts were also recovered. The BOC groups in 14
were cleaved (TFA) and the now free amino units were
acylated with 3-hydroxy-6-methoxyquinaldic acid11
(EDCI/HOBt). This resulted in formation of 15, i.e. the
bis-TBS ether of luzopeptin C. Desilylation could not
be conducted via the customary TBAF treatment,
because this reagent inflicted extensive damage to the
molecule. We attribute this to the basicity of TBAF and
to the vulnerability of intermediates incorporating mhv
esters and 4-hydroxy-piz subunits to basic agents. On
the other hand, exposure of 15 to the acidic HF/pyri-
dine complex provided fully synthetic 3, whose proper-
ties were identical to those described in the literature
for natural material. Luzopeptins A and B may be
obtained by selective acetylation of 3.1,6 Therefore, a
synthesis of 3 represents a formal synthesis of 1 and 2.
8. Boger, D. L.; Lederboer, M. W.; Kume, M.; Searcey, M.;
Jin, Q. J. Am. Chem. Soc. 1999, 121, 11375.
9. Chemistry of piperazic acids: (a) Ciufolini, M. A.; Xi, N.
J. Chem. Soc., Chem. Commun. 1994, 1867; (b) Ciufolini,
M. A.; Shimizu, T.; Swaminathan, S.; Xi, N. Tetrahedron
Lett. 1997, 38, 4947; (c) Xi, N.; Alemany, L. B.; Ciufolini,
M. A. J. Am. Chem. Soc. 1998, 120, 80; see also Ref. 4;
(d) Ciufolini, M. A.; Swaminathan, S. Tetrahedron Lett.
1989, 30, 3027; (e) Ciufolini, M. A.; Valognes, D.; Xi, N.
Tetrahedron Lett. 1999, 40, 3693.
10. (a) Ciufolini, M. A.; Xi, N. J. Org. Chem. 1997, 62, 2320;
(b) Xi, N.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36,
6595.
Acknowledgements
11. (a) Ciufolini, M. A.; Valognes, D.; Xi, N. Angew. Chem.
2000, 112, 2612; (b) Ciufolini, M. A.; Valognes, D.; Xi,
N. Angew. Chem., Int. Ed. Engl. 2000, 39, 2493.
12. See: Boger, D. L.; Schu¨le, G. J. Org. Chem. 1998, 63,
6421.
13. Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28,
4185.
14. For an excellent review of allyl-type blocking groups, see:
Kunz, H. Angew. Chem., Int. Ed. Engl. 1987, 26, 294 and
references cited therein.
The authors would like to thank the MENRT (Gradu-
ate Fellowship to D.V.), the CNRS, the Re´gion-Rhoˆne-
Alpes, the NIH (CA-55268), the NSF (CHE 95-26183),
and the R. A. Welch Foundation (C-1007). M.A.C. is a
fellow of the A. P. Sloan Foundation (1994–1998) and
the recipient of a Merck Academic Development
Award (2000).
15. Residual Ph3PꢀO in this intermediate does not seem to
interfere with subsequent coupling operations, and
indeed, it might even assist them, by analogy with the
behavior of certain N-oxides. See: Efimov, V. A.;
Chakhmakhcheva, O. G.; Ovchinnikov, Y. A. Nucleic
Acids Res. 1985, 13, 3651.
References
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F.; Tsuno, T.; Koshiyama, H.; Naito, T.; Kawaguchi, H.
J. Am. Chem. Soc. 1981, 103, 1241; (b) Arnold, E.;
Clardy, J. J. Am. Chem. Soc. 1981, 103, 1243 and refer-
.
.