Total synthesis of piperazimycin a: a cytotoxic cyclic hexadepsipeptide

Article abstract of DOI:10.1002/anie.200904603

Pied piper: The first total synthesis of the title compound 1, a potent cytotoxic natural product has been achieved. The key elements include an efficient synthesis of the difficult-to-install (R,S)-gCIPip/ (S, S)-gOH Pip dipeptide fragment as well as mac

Full text of DOI:10.1002/anie.200904603

Angewandte
Chemie
DOI: 10.1002/anie.200904603
Natural Product Synthesis
Total Synthesis of Piperazimycin A: A Cytotoxic Cyclic
Hexadepsipeptide**
Wenhua Li, Jiangang Gan, and Dawei Ma*
Piperazimycin A (1, Figure 1) is a cyclic hexadepsipeptide
which was isolated from the fermentation broth of a
Streptomyces sp., cultivated from marine sediments near the
island of Guam by Fenical and co-workers in 2007.[1] When
Structurally, piperazimycin A is an 18-membered macro-
cycle which is composed of a hydroxyacetic acid and five rare
amino acids. These amino acid residues include an (S)-a-
methylserine, a novel (S)-2-amino-8-methyl-4,6-nonadienoic
acid (S-AMNA), two g-hydroxypiperazic acids ((S,S)-
gOHPip and (R,R)-gOHPip), and one g-chloropiperazic
acid ((R,S)-gClPip). The g-substituted piperazic acid residues
have also been found in other antitumor cyclodepsipeptides
such as polyoxypeptins,[2] and antibiotic cyclodepsipeptides
such as monamycins,[3] himastatin,[4] lydiamycins,[5] and denti-
gerumycin.[6] The total synthesis of piperazic acid containing
natural products has received much attention during the past
decades.[7–9] Although some cyclodepsipeptides with the
g-substituted piperazic acid residues have been synthesized
successfully,[9c,d,g] none of them contain a dipeptide unit having
two piperazic acid residues (such as (R,S)-gClPip-(S,S)-
gOHPip in piperazimycin A). This difficult-to-install dipep-
tide presents a new synthetic challenge. Indeed, we have
prepared both the protected (R,S)-gClPip and (S,S)-gOHPip
units, but failed in installing them under various conditions,
especially using acid chlorides as coupling reagents.[10]
Accordingly, we planned to assemble this section of the
molecule by forming two piperazine rings only after the
connection of their precursors,[11] as indicated in Figure 1.
Since the ester part of this molecule is the only less sterically
hindered site, we decided to carry out the macrocyclization
through an ester bond formation.
The synthetic routes to requisite fragments 6 and 8 are
illustrated in Scheme 1. Treatment of the known lactone 2[12,13]
with LiHMDS and subsequent trapping of the resulting anion
with MoOPH[14] gave the desired trans-alcohol 3 in 73% yield
(79% brsm) with a 6:1 diastereoselectivity. The trans-alcohol
3 was reacted with triflic anhydride, and then exposed to
benzyl carbazate to afford hydrazide 4 in 81% yield.[15]
Protection of 4 with TrocCl led to formation of 5, which
upon saponification and subsequent methylation provided a
methyl ester, which was chlorinated using Ph3P and CCl4 to
deliver 6.
Figure 1. Structure of piperazimycin A and its bond disconnection
analysis.
screened using the National Cancer Instituteꢀs panel of 60
cancer cell lines, piperazimycin A exhibited in vitro cytotox-
icity toward multiple tumor cell lines with a mean GI50 value
of 100 nm.[1] Additional analysis revealed that this compound
had a nearly three-fold more potent activity against solid
tumors than against the leukemia cell lines tested. This
selectivity is not enough to support the development piper-
azimycin A for the treatment of cancer because of the general
cytotoxicity. Structure-activity relationship (SAR) studies of
this natural product would not only be able to overcome this
drawback, but also open a new avenue for exploring the
possible mode of action of this compound. However, before
comprehensive SAR studies can become a reality, an efficient
total synthesis of piperazimycin A is required. Herein, we
disclose the first total synthesis of this natural product.
In a parallel procedure, the enantiomer of trans-alcohol 3
(ent-3) was reacted with Tf2O and then treated with tert-butyl
carbazate to give hydrazide 7 in 88% yield. Removal of the
TBDPS ether in 7 by reaction with TBAF and AcOH
provided alcohol 8 in quantitative yield. These fragments
could then used to assemble the required (R,S)-gClPip/(S,S)-
gOHPip fragments (see below). Notably, 6 and 8 could be
easily converted into protected g-hydroxypiperazic acid and
g-chloropiperazic acid, respectively. Although several groups
have reported their efforts for assembling these g-substituted
piperazic acids,[9] our method apparently represents one of the
simplest procedures.
[*] W. Li, Dr. J. Gan, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry,
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-6416-6128
E-mail: madw@mail.sioc.ac.cn
[**] We are grateful to the Chinese Academy of Sciences, the National
Natural Science Foundation of China (grant no. 20632050 and
20621062), and the Ministry of Science and Technology of China
(grant no. 2010CB833200) for their financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904603.
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Scheme 1. Reagents and conditions: a) LiHMDS, THF, ꢀ788C; then
MoOPH, ꢀ78!ꢀ308C, 73%, 79% brsm; b) Tf2O, 2,6-lutidine, CH2Cl2,
08C; then benzyl carbazate, 2,6-lutidine, reflux, 81%; c) TrocCl, aq
NaHCO3, CHCl3, 08C!RT, 95%; d) aq LiOH, THF, 08C; then MeI,
DMF, 69%; e) PPh3, CCl4, reflux, 86%; f) Tf2O, 2,6-lutidine, CH2Cl2,
08C; then tert-butyl carbazate, 2,6-lutidine, reflux, 88%; g) TBAF,
HOAc, THF, quant. TBDPS=tert-butyldiphenylsilyl; Cbz=benzyloxy-
carbonyl; Troc=2,2,2-trichloroethoxycarbonyl; Boc=tert-butyloxycar-
bonyl; HMDS=hexamethyldisilazane; MoOPH=
Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide);
brsm=based on recovered starting material; Tf=trifluromethanesul-
fonyl; Troc=2,2,2-trichloroethoxycarbonyl; TBAF=tetra-n-butylammo-
nium fluoride.
Scheme 2. Reagents and conditions: a) aq LiOH, THF, 08C; b) oxalyl
chloride, DMF, CH2Cl2; c) 8, K2CO3, CH2Cl2, 08C, 74%; d) Tf2O, 2,6-
lutidine, CH2Cl2, 08C; then CF3CO2H; e) aq LiOH, THF, 08C; f) allylic
bromide, KHCO3, DMF, 67% yield for three steps; g) Ac2O, pyridine,
DMAP, CH2Cl2, 08C!RT, 97%; h) [Pd(PPh3)4], N-methylaniline, THF;
i) 12, HATU, HOAt, iPr2NEt, CH2Cl2, 90% yield for two steps; j) Zn,
1m KH2PO4, THF, 97%; k) Pd(OH)2, H2, FmocOSu, NaHCO3, MeOH,
74%. DMF=N,N-dimethylformamide; DMAP=4-dimethylaminopyri-
dine; MOM=methoxymethyl; HATU=O-(7-azabenzotriazol-1-yl)-
N,N,N’,N’-tetramethyluronium hexafluoro-phosphate; HOAt=
1-hydroxyazobenzotriazole; Fmoc=9-fluorenylmethyloxycarbonyl;
Su=succinimide.
Methyl ester 6 was saponified and the resulting acid was
treated with oxalyl chloride to afford the acyl chloride, which
was then coupled with 8 under the assistance of K2CO3 in
methylene chloride to give the N-acylation product 9 in 74%
yield (Scheme 2). The reaction conditions indicated here are
crucial for chemoselectivity because only the O-acylation
product was isolated when Et3N was used as a base.
Sulfonylation of the hydroxy group of 9 with Tf2O, removal
of the Boc protecting group with CF3CO2H, and then
intramolecular N-alkylation of the resulting amine gave the
piperazide, which was saponified and treated with allyl
bromide to provide allyl ester 10 in 67% overall yield. The
hydroxy group of 10 was protected with Ac2O to afford 11.
After cleavage of the allyl ester in 11 using [Pd(PPh3)4]/N-
methylaniline, the free acid was coupled with the (S)-a-
methylserine derivative 12 (prepared from (Z)-a-MeSer-
OMe,[16] see the Supporting Information) under HATU/
HOAt/iPr2NEt reaction conditions to give linear peptide 13.
Removal of the Troc group by reduction with activated zinc,
and exchange of the Cbz group for a Fmoc protecting group in
one step using Pd(OH)2/H2/FmocOSu/NaHCO3 afforded
amide 14, which was ready for condensation with the
(S)-AMNA fragment.
As depicted in Scheme 3, our construction of the
(S)-AMNA fragment started with bromination of the allyl
alcohol 15.[17] The allyl bromide was reacted with nBu3P, and
then treated with NaHMDS to provide an ylide, which was
reacted with aldehyde 16[18] to afford trans,trans-diene 17 in
70% yield as a single isomer. Using the double Boc-protected
aldehyde 16 in the Wittig reaction was found to be essential
for the exclusive production of 17, because low yield and
stereoselectivity were observed when a mono-Boc-protected
Scheme 3. Reagents and conditions: a) PBr3, Et2O, ꢀ308C to RT;
b) nBu3P, Et2O, 84% yield for two steps; c) NaHMDS, THF, ꢀ788C,
then 16, ꢀ788C, 70%; d) CF3CO2H, CH2Cl2; e) TrocCl, aq Na2CO3,
CHCl3, 08C!RT; f) aq LiOH, THF, 08C, quant. for three steps;
g) oxalyl chloride, DMF, CH2Cl2; h) 14, K2CO3, CH2Cl2, 08C, 75%;
i) TBAF, HOAc, THF, 65%, 98% brsm; j) PPh3, DEAD, THF, reflux,
98%. DEAD=diethylazodicarboxylate.
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aldehyde was employed. The additional Boc group might
increase the steric bulk of the substrate and prevent isomer-
ization of the intermediate oxaphosphetane, thereby giving
better stereoselectivity. After removal of the Boc group with
CF3CO2H, the liberated amine was reacted with TrocCl to
afford the Troc-protected amino ester, which was then
hydrolyzed with aqueous LiOH to provide amino acid 18.
Treatment of 18 with oxalyl chloride and subsequent coupling
of the acyl chloride with the hydrazide 14 gave amide 19 in
75% yield. Notably, 14, having two free NH groups at the
piperazic unit and the terminally monoprotected a-hydrazino
amide unit, was able to couple with the acyl chloride. The
exclusive formation of 19 clearly indicates that the free
piperazic NH group is much less reactive than free hydrazide
NH group. The subtle difference in the both electronic and
steric effects could account for this phenomenon.
To obtain the second piperazine ring, the TBDPS
protecting group in 19 needed to be removed first, but this
was challenging because both the base sensitive Fmoc and
acid sensitive MOM were present. After performing experi-
ments, we were pleased to find that this deprotection could be
accomplished by treatment of 19 with TBAF (2 equiv) and
AcOH (8 equiv) in THF. In this case the desired alcohol 20
was isolated in 65% yield (98% brsm). For the closure of the
piperazine ring, we initially attempted to use a sequence of
hydroxy-group activation and subsequent intramolecular
N-alkylation, but unfortunately we encountered problems
when screening reagents to remove the Fmoc group. To our
delight, when we executed Mitsunobu conditions,[19] alcohol
20 was converted into the desired tetrapeptide 21 in almost
quantitative yield. This transformation contains two steps: an
intramolecular substitution and the removal of the Fmoc
group, which has not yet been reported. Obviously, this
method could also be used to assemble related piperazic acid
derivatives.
Scheme 4. Reagents and conditions: a) Tf2O, 2,6-lutidine, CH2Cl2, 08C;
then 2,2,2-trichloroethyl carbazate, 2,6-lutidine, reflux, 75%; b) TBAF,
HOAc, THF, 98%; c) 24, K2CO3, CH2Cl2, 08C, 80%; d) Tf2O, 2,6-
lutidine, CH2Cl2, 08C; e) Zn, 1m KH2PO4, THF, 85% for two steps;
f) aq LiOH, THF, 08C; g) allylic bromide, KHCO3, DMF; h) Ac2O,
pyridine, DMAP, CH2Cl2, 08C to RT, 90% for three steps.
With the tetrapeptide 21 in hand, the construction of the
dipeptide fragment 27 became our next task. Treatment of
trans-alcohol 3 with triflic anhydride, and then exposure of the
resulting triflate to 2,2,2-trichloroethyl carbazate[20] provided
hydrazide 22 in 75% yield (Scheme 4). Removal of the
TBDPS ether afforded alcohol 23, which was coupled with
acid chloride 24[21] to give the N-acylation product 25 in 80%
yield. Sulfonylation of the hydroxy group of 25 with Tf2O,
subsequent removal of the Troc protecting group to deliver
the amine, and then intramolecular N-alkylation of the amine
gave piperazide 26 in 85% overall yield. After saponification
of 26, the liberated acid was treated with allyl bromide and
acetic anhydride to give allyl ester 27 in 90% overall yield.
The connection of the tetrapeptide 21 with the dipeptide
27 and the completion of the synthesis are depicted in
Scheme 5. Treatment of 21 with activated zinc afforded an
amine, which was then coupled with the acid released from
allyl ester 27 to give linear peptide 28 in 80% yield. The stage
was now set for the crucial macrocyclization, and we planned
to use a substitutive macrolactonization strategy which was
initially reported by Kellogg and co-workers to close the
macrocycle.[22] Accordingly, removal of the TBDPS ether in
28 afforded an alcohol, which was exposed to triphenylphos-
phine and hexachloroacetone (PPh3/HCA)[23] to provide
Scheme 5. Reagents and conditions: a) Zn, 1m KH2PO4, THF; b) [Pd-
(PPh3)4], N-methylaniline, THF, quant.; c) HATU, HOAt, iPr2NEt,
CH2Cl2, 80% yield from 21; d) TBAF, HOAc, THF, quant.; e) PPh3,
HCA, THF, 08C!RT, 89%; f) aq LiOH, THF, 08C, 95%; g) NaI,
K2CO3, DMF, 408C, 79%; h) TMSCl, TBAB, BuSH, CH2Cl2, 08C!RT,
78%. HCA=hexachloroacetone; TMS=trimethylsilyl; TBAB=tetra-n-
butylammonium bromide.
chloride 29 in 89% yield. The methyl ester and acetyl
protecting groups in 29 were carefully removed by saponifi-
cation. When treatment of the resulting acid under reported
reaction conditions (Cs2CO3, DMF, 808C),[22] the desired
macrocycle could not be detected, and only decomposition of
the acid was observed. Fortunately, when we treated this
intermediate with NaI and K2CO3 in DMF at 408C, we
isolated the desired cyclization product 30 in 79% yield. To
the best of our knowledge, this is the first report using the
substitutive macrolactonization strategy to synthesize natural
cyclic depsipeptides, eventhough it was reported 19 years ago.
Indeed, this success was essential for the completion of the
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Communications
2005, 46, 555; i) I. Mangion, N. Strotman, M. Drahl, J. Imbriglio,
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total synthesis of piperazimycin A because condensative
macrolactonization at this site using Yamaguchi,[24] Shiina,[25]
Mukaiyama,[26] Corey–Nicolaou,[27] and Mitsunobu condi-
tions[19] failed to give any desired product. This problem
might result from the low nucleophilicity of the hydroxy
group and the steric hindrance of the a-methylserine section.
Finally, the MOM ether of 30 was removed with TMSCl and
TBAB in the presence of nBuSH,[28] which acted as a cation
scavenger, producing piperazimycin A 1 in 78% yield. All
analytical data of the synthetic material were identical to
those of natural piperazimycin A.[1]
[8] For the total syntheses of other piperazic acid containing
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[9] For synthetic studies toward g-substituted piperazic acid con-
taining natural products, see: a) C. H. Hassall, K. L. Ramachan-
dran, Heterocycles 1977, 7, 119; b) K. J. Hale, N. Jogiya, S.
Manaviazar, Tetrahedron Lett. 1998, 39, 7163; c) T. M. Kame-
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In conclusion, we have accomplished the first total
synthesis of piperazimycin A (3.4% overall yield for 26
linear steps), which features a concise elaboration of its
difficult-to-install (R,S)-gClPip/(S,S)-gOHPip dipeptide frag-
ment and a macrocyclization through an SN2 reaction of an
N-2-chloroacetyl moiety with a carboxylate anion. The
former will be of benefit for synthesizing related natural
products like dentigerumycin and monamycins, while the
latter will prompt the application of the substitutive macro-
lactonization strategy in cyclodepsipeptide synthesis (spe-
cially for macrolactonization with the sterically hindered
acids). Our synthetic route could also be used for assembly of
piperazimycin A analogues, thereby exploring its structure-
activity relationship. Investigations in this direction are
actively being pursued in our laboratory and the results will
be disclosed in due course.[29]
Received: August 18, 2009
Published online: October 16, 2009
Keywords: antitumor activity · depsipeptides · macrocyclization ·
.
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[11] An analogous synthetic strategy was used for assembly of the
dehydropiperazic acids present in the luzopeptins. See referen-
ce [8f].
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