Total synthesis of padanamides A and B

Article abstract of DOI:10.1039/c3cc00178d

The first total syntheses of padanamides A and B have been achieved, unambiguously confirming their structures. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc00178d

Chemical Communications
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Volume 49 | Number 29 | 14 April 2013 | Pages 2945–3060
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COMMUNICATION
Ligong Chen, Zhengshuang Xu, Tao Ye et al.
Total synthesis of padanamides A and B

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Total synthesis of padanamides A and B†
Bohua Long,ab Shoubin Tang,c Ligong Chen,*a Shiwei Qu,c Bo Chen,c
Junyang Liu,c Anita R. Maguire,d Zhuo Wang,e Yuqing Liu,e Hui Zhang,c
Zhengshuang Xu*c and Tao Ye*bce
Cite this: Chem. Commun., 2013,
49, 2977
Received 8th January 2013,
Accepted 12th February 2013
DOI: 10.1039/c3cc00178d
www.rsc.org/chemcomm
The first total syntheses of padanamides A and B have been
achieved, unambiguously confirming their structures.
Many of the marine sediment-derived natural products1 possess
unique structural features rarely or never found among the com-
pounds isolated from the terrestrial sources. It is thus not surpris-
ing that their molecular modes of action are sometimes also
unique, prompting their investigation as potential targets for total
synthesis and drug development. The vast majority of secondary
metabolites, especially peptides, are derived from Streptomyces sp.
obtained from a marine sediment.2 We have been interested for
some time in marine peptides and view their synthesis as a key
route to structural modification and subsequent activity control.3
Here we report our efforts in the total synthesis of two highly
modified linear tetrapeptides, padanamides A and B (Scheme 1).
Padanamides A and B were isolated from laboratory cultures of
a Streptomyces sp. obtained from marine sediment collected near
the passage Padana Nahua in Papua New Guinea.4 The gross
chemical structures of padanamides A and B were established
using spectral techniques. Their absolute configurations were
Scheme 1 Retrosynthetic analysis of padanamides A (1) and B (2).
elucidated by a combination of spectroscopic, chemical degrada- and differ only in the last residue at the C-termini. Consequently, a
tion and single-crystal X-ray diffraction analyses. Padanamide B synthetic approach including the late-stage incorporation of
was cytotoxic to Jurkat cells, while padanamide A was suspected to either (S)-3-amino-2-oxopyrrolidine-1-carboxamide (Aopc) (4) or (S)-3-
inhibit cysteine and methionine biosynthesis.
aminopiperidine-2,6-dione (Apd) (5) at the C-termini would poten-
Our synthetic approach for padanamides A and B is outlined in tially access both 1 and 2. We envisaged that the key intermediate 3
Scheme 1. Padanamides A and B contain the same tripeptide unit (3) would arise from the assembly of acid 6 and amino alcohol 7.
The synthesis of key intermediate 3 commenced with the
a School of Chemical Engineering and Technology, Tianjin University,
preparation of 2R,3R-3-hydroxyleucine. Initial experiments for
the conversion of azidoester 95 to its corresponding acid 11
included protection of the secondary alcohol of 9 as its TBS ether
followed by saponification of the ethyl ester with lithium hydro-
xide, which led to extensively epimerization at the azide group-
bearing center. Gratifyingly, reversing the order of the protection
and hydrolysis sequence proved to be more successful. Thus,
treatment of azidoester 9 with lithium hydroxide afforded
carboxylic acid 10, which was then converted into the corre-
sponding silyl ether 11 in 72% overall yield by reaction with
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) in the
presence of 2,6-lutidine. No epimerization was observed in any of
Tianjin 300072, China. E-mail: lgchen@tju.edu.cn
b The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
c Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Xili,
Nanshan District, Shenzhen, 518055, China. E-mail: xuzs@pkusz.edu.cn
d Department of Chemistry and School of Pharmacy, Analytical and Biological
Chemistry Research Facility, University College Cork, Cork, Ireland.
E-mail: a.maguire@ucc.ie; Tel: +353-21-4902125
e Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong, China.
E-mail: bctaoye@inet.polyu.edu.hk; Tel: +852 34008722
† Electronic supplementary information (ESI) available: Full details of experimental pro-
cedures for compounds 1–7, 10–12, 14–15, 17–19, 21, 24, 26–28, 30–31 and NMR spectra
of compounds 1–7, 10–12, 14, 17–19, 21, 27–28 and 30. See DOI: 10.1039/c3cc00178d
c
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Scheme 2 (a) LiOH, THF–MeOH–H2O, 0 1C; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 1C;
(c) H2, Pd/C, MeOH, rt; (d) Fmoc–Cl, NaHCO3, THF–H2O, rt.
these two transformations. Reduction of the azide group of 11
followed by protection of the resulting amine with Fmoc–Cl
produced acid 12 in 82% overall yield (Scheme 2).
The synthesis of protected piperazic alcohol 14 began with the
enantiomerically pure (S)-tetrahydropyridazine 13,6 a known build-
ing block available from proline-catalyzed asymmetric a-hydrazina-
tion of 5-bromopentanal, protection of alcohol with TBS–Cl and
subsequent NaH-promoted cyclization. Two Cbz protecting groups
in 13 were removed under catalytic hydrogenation with 5% Pd–C to
give the corresponding cyclic hydrazine. The sterically less-hindered
Scheme 4 Attempted synthesis of dipeptide fragment. HATU: 2-(7-aza-1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOAT:
nitrogen atom of the resulting cyclic hydrazine was then reprotected 1-hydroxy-7-azabenzotriazole; PyBOP: benzotriazol-1-yl-oxytripyrrolidino-phos-
phonium hexafluorophosphate.
in situ with CbzCl to provide 14 in 86% yield. (S)-Tetrahydropyrida-
zine 13 is also easily converted into the corresponding piperazic
ester 15. Thus, removal of the TBS protecting group in 13 resulted in
an alcohol, which was converted into the corresponding carboxylic
acid via a TEMPO/NaClO/NaClO2 promoted oxidation process.7
After conversion of the carboxylic acid to its methyl ester, it was
then elaborated to piperazic ester 15 in 64% overall yield using an
identical strategy as described for 14 (Scheme 3). Literature pre-
cedent8 suggested that N-2 acylation of a piperazic-acid-derivative is
a challenging task due to the unusually poor nucleophilicity of the
piperazic ester. In order to take advantage of the higher reactivity of
the piperazic alcohol, we decided to employ 14 as the N-terminal
Scheme 5 (a) PPh3, THF–H2O, reflux; (b) Et3N, CH2Cl2, 0 1C–rt; (c) CSA, MeOH–
coupling partner for the synthesis of segment 6.
CH2Cl2; (d) NaIO4, RuCl3, acetone–H2O.
With 3-hydroxyleucine-derived acids 10–12 and piperazic alcohol
14 in hand, the coupling reactions were investigated. Unfortunately,
all attempts to effect condensation of acid 10 with piperazic alcohol 14 the boron (Z)-enolate derived from (S)-4-isopropyl-3-propionyl-2-
under the influence of coupling reagents (such as HATU (entry 1) and oxazolidinone (22) with N-Cbz-L-phenyl-alaninal 23.11 Hydrolysis of
PyBOP (entry 2)) or via a mixed anhydride (entry 3) did not succeed. the chiral auxiliary of 24 with LiOH–H2O2 followed by esterification
The reactions led only to decomposition of the starting material. of the resulting adduct with MeI, and Cbz hydrogenolysis, produced
Gratifyingly, silver cyanide-mediated coupling9 of 14 with acid chlor- 7 in 71% yield over three steps (Scheme 6). Condensation of acid 6
ides derived from either 11 or 12 proceeded smoothly, delivering with amine 7 via the mixed carbamic–carbonic anhydride gave rise
dipeptides 17 and 18 in 85% and 80% yield, respectively (Scheme 4). to 25 in 86% yield. Unexpectedly, attempted hydrogenolysis of the
The Staudinger reduction of azide 17 with PPh3 in THF–H2O was Cbz protecting group in 25 under a variety of reaction conditions
followed by a condensation of the resulting amine with acid resulted in decomposition of the starting material. We then elected
chloride 20 to afford tripeptide 21 in 68% overall yield for the two to cleave off the Cbz protecting group in 6 prior to coupling with
steps. Selective removal of the primary TBS group of 21 with CSA/ amine 7. Gratifyingly, this revised approach produced the tripeptide
MeOH followed by oxidation of the resulting hydroxyl group with unit 3 in 72% yield over two steps (Scheme 7).
NaIO4 in the presence of catalytic amounts of RuCl3 furnished
carboxylic acid 6 in 68% yield over the two steps (Scheme 5).
With the key intermediate 3 in hand, we next turned our atten-
tion to the synthesis of (S)-3-amino-2-oxopyrrolidine-1-carboxamide
Methyl ester of Ahmpp (7) was prepared from the known aldol (Aopc) (4) or (S)-3-aminopiperidine-2,6-dione (Apd) (5). Thus,
adduct 24 (ref. 10) through a diastereoselective syn aldol addition of treatment of the known lactam 27 with sodium hydride and
i
Scheme 3 (a) H2, Pd/C; (b) Cbz–Cl, Et3N, MeOH; (c) TBAF, THF; (d) TEMPO,
NaClO/NaClO2; (e) SOCl2, MeOH, À20 1C.
Scheme 6 (a) Bu2BOTf, Pr2NEt, CH2C12, 0 1C; then 23, À78 to 25 1C; (b) LiOH,
H2O2, THF–H2O; (c) NaHCO3, MeI, DMF; (d) H2, Pd/C, MeOH, 1 N HCl (aq.).
c
2978 Chem. Commun., 2013, 49, 2977--2979
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padanamide A; [a]2D5 À21.5, c 7.3, MeOH, for padanamide B), which
led us to conclude that synthetic 1 and 2 were of the same absolute
stereochemistry as natural padanamides A and B.
In summary, we have accomplished the total synthesis of padan-
amides A and B from the known azidoester 9 in 7.1 and 8.3% overall
yield, respectively, with the longest linear sequence of 12 steps. This
synthesis confirmed the structures of padanamides A and B. The
extension of this chemistry toward the synthesis of padanamide
analogues for further biological evaluation is underway and will be
reported in due course.
We acknowledge financial support from the Hong Kong
Research Grants Council (Projects: PolyU 5040/10P; PolyU 5037/
11P, PolyU 5020/12P); Fong Shu Fook Tong Foundation and Joyce
M. Kuok Foundation; The Hong Kong Polytechnic University
(PolyU 5636/08M; PolyU 5634/09M); The National Science Founda-
tion of China (21072007, 21133002 & 21272011); The Shenzhen
Bureau of Science, Technology & Information (JC200903160367A,
JC201005260102A, JC201005260220A, ZYC201105170351A and
ZD200806170044A).
Scheme 7 (a) ClCO2iBu, NMM, THF; then 7, À20 1C–rt; (b) H2, Pd/C, MeOH.
Scheme 8 (a) NaH, tert-butylisocyanate, THF, 0 1C; (b) TFA, anisole, D 16 h.
Notes and references
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tert-butylisocyanate in THF afforded urea 28 in 60% yield. Acidic
cleavage of both the tert-butyl and Cbz groups in 28 gave rise to the
required intermediate 4 in 80% yield (Scheme 8). (S)-N-Cbz-
a-aminoimide 5 was obtained in 67% yield in a two-step sequence
including a DCC-mediated intramolecular cyclization of N-Cbz-
L-glutamine leading to adduct 30, and subsequent hydrogenolytic
removal of the carboxybenzyl group (Scheme 9).
At this juncture, the time had arrived to assemble the key
intermediate 3 with Aopc (4) or Apd (5) leading to padanamides A
and B, respectively. Thus, saponification of the methyl ester of 3
followed by coupling with (S)-3-amino-2-oxopyrrolidine-1-carbox-
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condensation of 3 and 5 (Scheme 10). The spectral data for
synthetic 1 and 2 (1H, 13C NMR and HMRS) were identical with
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[a]2D5 À20.7, c 0.2, MeOH, for padanamide B) corresponded
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Scheme 10 (a) LiOH, THF–MeOH–H2O; (b) BOPCl, 4 or 5, HOAT, NMM, THF, 0 1C–rt,
18 h; (c) 40% HF, MeCN, 0 1C, 3 h. BOPCl: bis(2-oxo-3-oxazolidinyl)phosphinic chloride.
c
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Chem. Commun., 2013, 49, 2977--2979 2979