Total synthesis of (+)-azinothricin and (+)-kettapeptin

Article abstract of DOI:10.1021/ol802817t

(Chemical Equation Presented) Asymmetric total syntheses of (+)-azinothricin and (+)-kettapeptin have been completed through a common new pathway that exploits a highly chemoselective coupling reaction between the fully elaborated cyclodepsipeptide 5 and the glycal activated esters 3 and 4 at the final stages of both respective syntheses.

Full text of DOI:10.1021/ol802817t

ORGANIC
LETTERS
2009
Vol. 11, No. 3
733-736
Total Synthesis of (+)-Azinothricin and
(+)-Kettapeptin
Karl J. Hale,*,† Soraya Manaviazar,*,† Jonathan H. George,‡ Marcus A. Walters,‡
and Stephen M. Dalby‡
The School of Chemistry & Chemical Engineering, and the Centre for Cancer
Research and Cell Biology, Queen’s UniVersity Belfast (QUB), Stranmillis Road,
Belfast BT9 5AG, U.K., and The Christopher Ingold Laboratories, UCL, 20 Gordon
Street, London WC1H 0AJ, U.K.
k.j.hale@qub.ac.uk; s.manaViazar@qub.ac.uk
Received December 6, 2008
ABSTRACT
Asymmetric total syntheses of (+)-azinothricin and (+)-kettapeptin have been completed through a common new pathway that exploits a
highly chemoselective coupling reaction between the fully elaborated cyclodepsipeptide 5 and the glycal activated esters 3 and 4 at the final
stages of both respective syntheses.
(+)-Azinothricin1 is the founding member of a potent and
biologically intriguing family of antitumor antibiotics that
now include A83586C,2 citropeptin,3 GE3,4 and kettapeptin5
among their number.
As part of a longstanding effort to understand how the
A83586C/GE3/citropeptin and kettapeptin pyranylated cy-
clodepsipeptides function as antitumor agents,6 we became
interested in evaluating the anticancer properties of (+)-
azinothricin and (+)-kettapeptin with the aid of cDNA
microarray technology. However, due to the fact that natural
samples of (+)-azinothricin no longer exist and because we
also wished to biologically evaluate analogue structures, we
elected to synthesize both natural products chemically, by a
new and considerably shortened pathway to molecules of
the A83586C/azinothricin/kettapeptin class (see Scheme 1
for all three structures).
Our approach to these targets would dispense with
protecting groups at the final stages of each synthesis and
would attempt the chemoselective coupling of fragments 3
and 4 with 5 to obtain glycals 1 and 2, respectively.
Regioselective hydration at C(30) would thereafter finalize
both synthetic ventures (Scheme 1).
Regarding our tactics for constructing 5 and 6, a fragment
condensation between 7 and 8 would initiate proceedings.
A union between the resulting Fmoc-deprotected tetrapeptide
and acid chloride 9 would thereafter yield a suitably protected
linear hexapeptide. Its two Boc-protecting groups would then
† Queen’s University Belfast.
‡ Christopher Ingold Laboratories, UCL.
(1) Azinothricin isolation, structure determination, and initial antibiotic
screening: Maehr, H.; Liu, C.; Palleroni, N. J.; Smallheer, J.; Todaro, L.;
Williams, T. H.; Blount, J. F. J. Antibiot. 1986, 39, 17.
(2) A83586C: Smitka, T. A.; Deeter, J. B.; Hunt, A. H.; Mertz, F. P.;
Ellis, R. M.; Boeck, L. D.; Yao, R. C. J. Antibiot. 1988, 41, 726.
(3) Citropeptin: Nakagawa, M.; Hayakawa, Y.; Furihata, K.; Seto, H.
J. Antibiot. 1990, 43, 477.
(4) GE3: Sakai, Y.; Yoshida, T.; Tsujita, T.; Ochiai, K.; Agatsuma, T.;
Saitoh, Y.; Tanaka, F.; Akiyama, T.; Akinaga, S.; Mizukami, T. J. Antibiot.
1997, 50, 659.
(5) Kettapeptin: Maskey, R. P.; Fotso, S.; Sevvana, M.; Uson, I.; Grun-
Wollny, I.; Laatsch, H. J. Antibiot. 2006, 59, 309.
(6) A83586C synthesis: Hale, K. J.; Cai, J. Chem. Commun. 1997, 2319.
10.1021/ol802817t CCC: $40.75
Published on Web 01/06/2009
2009 American Chemical Society

regioselective hydroboration/oxidation, thioetherification, and
sulfide oxidation. Homoallylic alcohols 14 and 15 would
themselves be obtainable from enals 17 and 18 by Roush
asymmetric crotylboration8 with 16. An Evans asymmetric
aldol reaction9 and a Wittig olefination sequence would
suffice to secure 20 and 21 from the precursors 22/23 and
24.
Scheme 1. Retrosynthetic Strategy for the Asymmetric Total
Synthesis of (+)-Azinothricin and (+)-Kettapeptin
Initial attention focused upon the preparation of aldehydes
20 and 21 via Evans asymmetric aldol chemistry9 (Scheme
2). The synthesis of aldehyde 21 had previously been
published by our group in 200510 in another context. The
route to 20 proceeded analogously, setting off with a syn
aldol reaction between 22 and 24 to access 25 as essentially
a single diastereoisomer in 85% yield. It was then subjected
to a Weinreb amidation11 to obtain 26 which was O-silylated
before being reduced with DIBAL-H to secure aldehyde 20.
Aldehydes 20 and 21 were individually converted to enals
17 and 18 by stereoselective Wittig olefination, DIBAL-H
reduction, and MnO2 oxidation. Roush crotylboration9 of 17
and 18, respectively, with 16 furnished 14 and 15 with a
2.3:1 level of selectivity in favor of the desired anti-
configured products. The individual alcohols 14 and 15 were
readily purified by SiO2 flash chromatography.
Following O-benzylation of 14 or 15 with p-methoxyben-
zyl trichloroacetimidate and catalytic TfOH in Et2O, regi-
oselective hydroboration/oxidation of the two less hindered
terminal alkenes in these products with 9-BBN and basic
H2O2 provided the desired individual primary alcohols 27
and 28 in good overall yield (71% and 73% yield, respec-
tively, over two steps). Sulfones 11 and 12 were each
prepared by thioetherification with Bu3P/(PhS)2 in DMF and
Oxone oxidation in THF/MeOH/H2O.
Although chiral aldehyde 10 had previously featured in our
original route to A83586C,6 a major flaw in our first-generation
synthesis of 1012 was the low regioselectivity (2:1 desired:
undesired product) we had obtained in the introduction of the
tertiary OPMB group by an O-p-methoxybenzylidene acetal
reduction tactic.12 Our new, second-generation pathway to 10
(Scheme 3) now overcomes all of these past difficulties by
applying a Trost Pd(0)-catalyzed asymmetric O-alkylation/
kinetic resolution reaction7 to racemic vinyl epoxide 13. With
PMBOH as the nucleophile and (R,R)-phosphine ligand 37 as
the key asymmetry-inducing additive, this process delivered the
desired alcohol 38 in good yield (74%) and excellent ee (95%).
Successive Swern and Pinnick13 oxidations converted 38 into
the acid 39 which was then O-methylated and ozonized to
provide aldehyde 10.
be removed, the resulting (3S)-piperazic acid acyl hydrazide
oxidatively converted to an acid, and a macrolactamization
effected between the D-threonine and (3S)-piperazic acid
residues. Further protecting group adjustment would then
provide 6 and 5.
Sulfones 11 and 12 were now metallated with n-BuLi in
THF, and the resulting anions individually condensed with
aldehyde 10 at -78 °C (Scheme 2). Swern oxidation and
(7) (a) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc.
1998, 120, 12702. (b) Trost, B. M.; Tang, W.; Schulte, J. Org. Lett. 2000,
2, 4013. (c) Trost, B. M.; Anderson, N. G. J. Am. Chem. Soc. 2002, 124,
14320. (d) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(8) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman,
R. L. J. Am. Chem. Soc. 1990, 112, 6339.
The activated esters 3 and 4 would derive from the
respective unions of 11 and 12 with aldehyde 10, following
further synthetic manipulation. Our favored pathway to 10
would apply a Trost asymmetric alcoholysis reaction7 to the
racemic vinyl epoxide 13 to introduce the requisite OPMB
stereocenter. Oxidative manipulation would thereafter com-
plete the route. Phenylsulfones 11 and 12 would emanate
from the alkenes 14 and 15 by O-p-methoxybenzylation,
(9) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(10) Dimopoulos, P.; George, J.; Manaviazar, S.; Tocher, D. A.; Hale,
K. J. Org. Lett. 2005, 7, 5377.
(11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
734
Org. Lett., Vol. 11, No. 3, 2009

Scheme 2
.
Routes Developed to Pyran Activated Esters 3 and 4
Scheme 3. Our New Asymmetric Route to Aldehyde 10
deployed in our original A83586C synthesis.6,12
Our new abridged pathway to 86 is shown in Scheme 4.
Major new advances include the direct preparation of the
acyl hydrazide 416 from (3S)-N(1)-Z-piperazic acid 4014
without protection of N(2).
Scheme 4. New Improved Route to Dipeptide 8
Our pathway to 50 (Scheme 5) began from Jager’s 2-O-
benzyl-D-threitol.15 Following regioselective O-isopropy-
lidenation with 1,1-dimethoxypropane and O-methylation
with NaH/MeI in DMF to obtain 46, the isopropylidene
group was detached, and the resulting diol 47 was oxidatively
cleaved. The intermediary aldehyde was then subjected to a
Pinnick oxidation13 to access acid 48. Hydrogenolytic
O-debenzylation of 48 with Pearlman’s catalyst provided the
chiral R-hydroxyacid needed for chemoselective O-allylation
with K2CO3/AllylBr in DMF. The product alcohol 49 was
subsequently converted to an O-triflate ester and this
subjected to an Ottenheijm SN2-type displacement16 with
BnONH2 to obtain 50.
A silver cyanide assisted amidation6 was now effected
between alkoxyamine 50 and acid chloride 51 to procure
dipeptide 52 in 84% yield. It underwent clean O-deallylation
under neutral conditions with phenylsilane and catalytic
17
Al/Hg amalgam reduction thereafter procured the ꢀ-ke-
toesters 29 and 30. The less hindered and more electron-
rich secondary OPMB group was now selectively deprotected
from 29 and 30 with DDQ in aqueous CH2Cl2, and the
resulting hydroxyketones were dehydrated with PPTS in
MeOH at 60 °C. Glycals 31 and 32 were then taken forward
to the activated esters 3 and 4 by analogous reactions to those
Pd(PPh3)4 to produce the acid 7 needed for our BOP-Cl
coupling with 8. The latter proceeded in 79% yield from 43
and afforded the tetrapeptide 53 after Et2NH-induced cleav-
age of the Fmoc group.
A third silver cyanide mediated amidation was now
implemented, on this occasion, with 53 and acid chloride
9;6 it delivered 54 in 55% yield after purification. Both Boc
Org. Lett., Vol. 11, No. 3, 2009
735

Scheme 5
.
Route Used to Secure 50 and Linear
Hexadepsipeptide 55
Scheme 6. Endgames for (+)-Azinothricin and (+)-Kettapeptin
The subsequent individual couplings of 5 with 3 and 4
took place cleanly to give 1 and 2, respectively (Scheme 6).
After individual chromatographic purification and dissolution
in CDCl3, compound 1 gave rise to (+)-azinothricin in 42%
yield from 6, while compound 2 produced (+)-kettapeptin
in 32% yield from 6.
In summary, the first total syntheses of (+)-azinothricin
and (+)-kettapeptin have been achieved by a new unified
synthetic strategy that cuts 12 steps off the original route to
molecules of the A83586C class.6
Acknowledgment. We thank Novartis Pharma AG and
Queen’s University Belfast for financial support.
Supporting Information Available: Full experimental
1
procedures, spectral data, and copies of 500 MHz H and
125 MHz 13C NMR spectra are provided along with IR
spectra and HRMS data. This material is available free of
charge via the Internet at http://pubs.acs.org.
groups were now removed from 54 with TFA, and the acyl
hydrazide was oxidatively hydrolyzed with N-bromosuccin-
imide (NBS) in aqueous THF.6 The hexapeptide salt 55
thereafter cyclized with HATU18 under high dilution condi-
tions over several days (Scheme 6). The latter reaction
proceeded in 45% overall yield for these last three steps.
The next phase of the synthesis was deprotection of the Troc
group from 56 with Zn dust in acetic acid. N-Acylation with
PhCH2OC(O)Cl thereafter furnished 6 in 49% yield for the
last two steps, with SiO2 flash chromatography allowing 6
to be purified to very high standards. The time had now come
to deprotect 6 to secure 5; the desired hydrogenolysis
proceeded successfully in HCl/MeOH with 10% Pd on C.
OL802817T
(12) Hale, K. J.; Cai, J. Tetrahedron Lett. 1996, 37, 4233.
(13) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
(14) (a) N(1)-Z-Piz: Adams, C. E.; Aguilar, D.; Hertel, S.; Knight, W. H.;
Paterson, J. Synth. Commun. 1988, 18, 2225. (b) (3S)- and (3R)-Piz: Hale,
K. J.; Cai, J.; Delisser, V.; Manaviazar, S.; Peak. S. A.; Bhatia, G. S.; Collins,
T. C.; Jogiya, N. Tetrahedron 1996, 52, 1047.
(15) Steuer, B.; Lieberknecht, W. A.; Jager, V.; Bullock, J. P.; Hegedus,
L. S. Org. Synth. 1996, 74, 1.
(16) Feenstra, R. W.; Stokkingreef, E. H. M.; Nivard, R. J. F.;
Ottenheijm, H. C. J. Tetrahedron 1988, 44, 5583.
(17) Dessolin, M.; Guillerez, M.-G.; Thieriet, N.; Guibe, F.; Loffet, A.
Tetrahedron Lett. 1995, 36, 5741.
(18) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4937.
736
Org. Lett., Vol. 11, No. 3, 2009