Total syntheses of amythiamicins A, B and C

Article abstract of DOI:10.1039/b805069b

Total syntheses of the thiopeptide antibiotics amythiamicins A, B and C are reported. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805069b

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Total syntheses of amythiamicins A, B and Cwz
K. C. Nicolaou,*abc Dattatraya H. Dethea and David Y.-K. Chen*a
Received (in Cambridge, UK) 25th March 2008, Accepted 11th April 2008
First published as an Advance Article on the web 8th May 2008
DOI: 10.1039/b805069b
Total syntheses of the thiopeptide antibiotics amythiamicins A,
B and C are reported.
Isolated from a strain of Amycolatopsis sp. MI481-42F4,
amythiamicins A, B and C1 (1–3, Fig. 1) are members of the
trisubstituted pyridine subclass of the thiopeptide family of
antibiotics.2 In addition to their impressive antibiotic properties
against Gram-positive bacteria, including MRSA,1a these sub-
stances also exhibit activity against Plasmodium falciparum, the
causative parasite responsible for malarial infections.3 The anti-
parasitic properties of these thiopeptides are believed to be
exerted through inhibition of protein synthesis by binding to
elongation factor EF-Tu. This mechanism of action is similar to
that exhibited by GE2270A but with a different binding site.3 In
Fig. 1 Molecular structures and retrosynthetic analysis of amythia-
view of their novel molecular architectures and mechanism of
action, amythiamicins A, B and C (1–3) were deemed worthy
synthetic targets.4 In this communication we report expedient
total syntheses of all three natural products 1–3 through appli-
cation of our recently developed synthetic technologies5 for the
construction of thiopeptide antibiotics.
micins A (1), B (2) and C (3). (a) Hetero-Diels–Alder dimerization; (b)
regioselective macrolactamization.
of diastereomers) for the two steps. Exposure of thiazolidine 9
to the previously established reagent mix (Ag2CO3, DBU,
BnNH2, py) under the optimized reaction conditions
(ꢀ12 1C, 1 h)5d smoothly delivered dehydropiperidine 11 in
51% yield as a ca. 1 : 1 mixture of diastereoisomers through
the intermediacy of heterodiene 10. Finally, oxidative aroma-
tization (DBU, EtOAc) with concomitant extrusion of ammo-
nia gave trithiazolyl pyridine 12 in 36% yield.
Our synthetic strategy towards the amythiamicins features
application of the powerful hetero-Diels–Alder dimerization
process,5 followed by oxidative aromatization to assemble the
trisubstituted pyridine core of the molecule. A subsequent
regioselective macrocyclization engaging the C1 carboxylic
acid terminus was envisaged for the construction of the
29-membered macrolactam ring of the amythiamicins while
at the same time activating the C10 terminus of the growing
molecule so as to facilitate side chain attachment, thereby
enabling a ‘‘one-pot’’, tandem bis-amidation process.5d,6
The synthesis of the required thiazolidine 9 and its dimer-
ization to trisubstituted pyridine 12 is summarized in Scheme
1. Thus, coupling of a-bromo ketone 45d with thioamide 57 in
the presence of TFAA and pyridine gave bis-thiazole 6 in 78%
yield. Reduction of the ethyl ester group within 6 (DIBAL-H)
(85% yield) followed by condensation with amino thiol TFA
salt 85b afforded thiazolidine 9 in 80% yield (ca. 7 : 3 mixture
The other major fragment required for the total synthesis of
the amythiamicin molecule, tripeptide carboxylic acid 15, was
prepared by the coupling of carboxylic acid 135d with glycine
methyl ester (HATU, iPr2NEt), followed by saponification
(LiOH) as shown in Scheme 2 (54% overall yield).
The union of trithiazolyl pyridine 12 and tripeptide car-
boxylic acid 15 and further elaboration to amythiamicins A
(1), B (2) and C (3) are shown in Scheme 3. Thus, removal of
the Boc group from 12 (TFA) followed by coupling of the
resulting amine (16) with carboxylic acid 15 (HATU, iPr2NEt)
afforded hexathiazole pyridine 17 in 60% yield for the two
steps from 12. Exposure of di-ester 17 to excess LiOH in
aqueous DME followed by treatment with TFA furnished
amino di-acid 19 via Boc di-acid 18, setting the stage for the
anticipated ‘‘one-pot’’ sequential intramolecular/intermolecu-
lar bis-amidation. In the event, and under previously esta-
blished conditions,5d,6 subjecting 19 to excess HATU and
a Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and
Engineering Sciences (ICES), Agency for Science, Technology and
Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08
Singapore 138667. E-mail: david_chen@ices.a-star.edu.sg
b Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, USA. E-mail: kcn@scripps.edu
c Department of Chemistry and Biochemistry, University of California,
San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
w Dedicated to Andrew B. Holmes on the occasion of his 65th birth-
day.
iPr2NEt under high dilution conditions (0.001
M in
CH2Cl2–DMF 4 : 1) induced regioselective macrolactamiza-
tion, affording the presumed activated macrolactam inter-
mediate 20, which was treated, without isolation, with the
HCl salt of prolinamide–serine conjugate (21),8 delivering
amythiamicin B (2) in 25% yield over the three steps from
z Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/b805069b
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Scheme 1 Synthesis of trithiazolyl pyridine 12. Reagents and condi-
tions: (a) 4 (1.5 equiv.), 4 A MS, DMF, 0 - 25 1C, 18 h; then TFAA
(1.5 equiv.), pyridine (3.0 equiv.), CH2Cl2, 0 1C, 3 h, 78%; (b) DIBAL-
H (1.0 M in toluene, 2.0 equiv.), toluene, ꢀ78 1C, 3 h, 85%; (c) 8ꢂTFA
(1.2 equiv.), KHCO3 (10.0 equiv.), MeOH–H2O (3.75 : 1), 25 1C, 16 h,
80% (ca. 3 : 1 mixture of diastereoisomers); (d) Ag2CO3 (1.0 equiv.),
BnNH2 (2.0 equiv.), DBU (0.25 equiv.), pyridine, ꢀ12 1C, 1 h; then
H2O–EtOAc (1 : 1), 25 1C, 1 h, 51% (ca. 1 : 1 mixture of diastereoi-
somers); (e) DBU (5.0 equiv.), EtOAc, reflux, 5 h, 36%. DMF =
N,N0-dimethylformamide; TFA = trifluoroacetic acid; TFAA =
trifluoroacetic anhydride; DIBAL-H = diisobutylaluminium hydride;
Bn = benzyl; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Scheme 3 Total syntheses of amythiamicins A (1), B (2) and C (3).
Reagents and conditions: (a) TFA–CH2Cl2 (1 : 4), 25 1C, 2 h; (b) 15
(1.2 equiv.), HATU (1.5 equiv.), iPr2NEt (5.0 equiv.), CH2Cl2, 25 1C,
16 h, 60% for two steps from 12; (c) LiOH (10.0 equiv.), DME–H2O
(4 : 1), 5 h; (d) TFA–CH2Cl2 (1 : 4), 25 1C, 2 h; (e) HATU (5.0 equiv.),
iPr2NEt (10.0 equiv.), CH2Cl2–DMF (4 : 1) (0.001 M), 0 1C, 3 h; then
21 (5.0 equiv.), 0 - 25 1C, 24 h, 25% for the three steps; (f) DAST (1.5
equiv.), CH2Cl2, ꢀ25 1C, 1 h, 70%; (g) aq. HCl, 110 1C, 1 h, 60%.
DAST = N,N0-diethylaminosulfur trifluoride.
di-ester 17. Exposure of 2 to DAST converted its hydroxy
amide moiety to the corresponding thiazoline unit, thus
furnishing amythiamicin A (1) in 70% yield. The latter was
then transformed to amythiamicin C (3) through the action of
aq. HCl by a literature procedure.1c Synthetic 1–3 exhibited
identical physical properties (1H and 13C NMR, mass spectra
the hetero-Diels–Alder dimerization approach to this type of
structural motif.
We thank Ms Doris Tan (ICES) for high resolution mass
spectrometric (HRMS) assistance. Financial support for this
work was provided by A*STAR, Singapore.
1
for 1 and 2; H NMR spectra for 3) to those reported for the
corresponding natural products.1c
Notable for their brevity and convergency, the described
total syntheses allow facile entries to these antibiotics (1–3)
and their analogs, and provide yet another demonstration of
Notes and references
1 (a) K. Shimanaka, N. Kinoshita, H. Iinuma, M. Hamada and T.
Takeuchi, J. Antibiot., 1994, 47, 668–674; (b) K. Shimanaka, Y.
Takahashi, H. Iinuma, H. Naganawa and T. Takeuchi, J. Anti-
biot., 1994, 47, 1145–1152; (c) K. Shimanaka, Y. Takahashi, H.
Iinuma, H. Naganawa and T. Takeuchi, J. Antibiot., 1994, 47,
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3 B. Clough, K. Rangachari, M. Strath, P. R. Preiser and R. J. M.
Wilson, Protist, 1999, 150, 189–195.
Scheme 2 Preparation of tripeptide carboxylic acid fragment 15.
Reagents and conditions: (a) glycine methyl ester (1.2 equiv.), HATU
(1.2 equiv.), iPr2NEt (5.0 equiv.), CH2Cl2, 25 1C, 12 h, 60%; (b) LiOH
(5.0 equiv.), DME–H2O (4 : 1), 25 1C, 2 h, 90%. HATU =
4 For total synthesis of amythiamicin D, see: (a) R. A. Hughes, S. P.
Thompson, L. Alcaraz and C. J. Moody, J. Am. Chem. Soc., 2005,
127, 15644–15651; (b) R. A. Hughes, S. P. Thompson, L. Alcaraz
and C. J. Moody, Chem. Commun., 2004, 946–948.
5 (a) K. C. Nicolaou, M. Zak, B. S. Safina, A. A. Estrada, S. H. Lee
and M. Nevalainen, J. Am. Chem. Soc., 2005, 127, 11176–11183; (b)
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluoro-
phosphate; DME = ethylene glycol dimethyl ether.
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7 Prepared in two steps from Boc-L-valine: (i) DCC, N-hydroxysuc-
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¨
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This journal is The Royal Society of Chemistry 2008
2634 | Chem. Commun., 2008, 2632–2634