Total synthesis of Oxazolomycin a

Article abstract of DOI:10.1021/ol202306d

The first total synthesis of oxazolomycin A, a structurally novel oxazole polyene γ-lactam/β-lactone antibiotic, is described. Key features include the stereocontrolled construction of the right-hand heterocyclic core bytaking advantage of an In(III)-cata

Full text of DOI:10.1021/ol202306d

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5398–5401
Total Synthesis of Oxazolomycin A
Kohei Eto, Madoka Yoshino, Keisuke Takahashi, Jun Ishihara, and
Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University,
Nagasaki 852-8521, Japan
susumi@nagasaki-u.ac.jp
Received August 25, 2011
ABSTRACT
The first total synthesis of oxazolomycin A, a structurally novel oxazole polyene γ-lactam/β-lactone antibiotic, is described. Key features include
the stereocontrolled construction of the right-hand heterocyclic core by taking advantage of an In(III)-catalyzed Conia-ene type cyclization and the
asymmetric synthesis of the left-hand segment starting with a Cinchona alkaloid-catalyzed cyclocondensation of an aldehyde with an acid
chloride.
Oxazolomycin A (1), first isolated from a strain of
Streptomyces together with neooxazolomycin in 1985 by
Uemura et al.,1 is the parent member of a family of
structurally novel polyene lactone-lactam antibiotics.2
Other members identified to date include oxazolomycins
B and C,3 16-methyloxazolomycin,4 curromycins A and
B,5 KSM-2690 B and C,6 and lajollamycin.7
with the pharmacophores of omuralide and salinospora-
mide A, representative 20S proteasome inhibitors.8 The
intriguing biological properties and structural challenges
have made oxazolomycins and their analogs9 attractive
targets for synthesis. Although a number of methodologies
for the construction of each left-hand polyene part10 and
right-hand heterocyclic core11 have been developed, the
These oxazolomycins exhibit wide ranging and potent
antibacterial and antiviral activities as well as in vivo
antitumor activity.2 The characteristic β-lactone-γ-lactam
motif draws much attention due to the structural similarity
(9) Bagwell, C. L.; Molony, M. G.; Thompson, A. L. Bioorg. Med.
Chem. Lett. 2008, 18, 4081. (b) Bagwell, C. L.; Molony, M. G.; Yaqoob,
M. Bioorg. Med. Chem. Lett. 2010, 20, 2090.
(10) (a) Kende, A. S.; Kawamura, K.; Orwat, M. J. Tetrahedron Lett.
ꢀ
1989, 30, 5821. (b) Henaff, N.; Whiting, A. Org. Lett. 1999, 6, 1137. (c)
ꢀ
Henaff, N.; Whiting, A. Tetrahedron 2000, 56, 5193. (d) Bulger, P. G.;
(1) (a) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.;
Katayama, C.; Iwadare, S.; Shizuri, Y.; Mitomo, R.; Nakano, F.;
Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1073. (b) Takahashi, K.;
Kawabata, M.; Uemura, D.; Iwadare, S.; Mitomo, R.; Nakano, F.;
Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1077.
(2) For a review, see: Moloney, M. G.; Trippier, P. C.; Yaqoob, M.;
Wang, Z. Curr. Drug Discovery Technol. 2004, 1, 181.
(3) Kanzaki, H.; Wada, K.; Nitoda, T.; Kawazu, K. Biosci. Biotech-
nol. Biochem. 1998, 62, 438.
(4) (a) Ryu, G.; Hwang, S.; Kim, S.-K. J. Antibiot. 1997, 50, 1064. (b)
Ryu, G.; Kim, S.-K. J. Antibiot. 1999, 52, 193.
(5) Ogura, M.; Nakayama, H.; Furihata, K.; Shimazu, A.; Seto, H.;
Otake, N. J. Antibiot. 1985, 38, 669.
(6) Otani, T.; Yoshida, K. I.; Kubota, H.; Kawai, S.; Ito, S.; Hori, H.;
Ishiyama, T.; Oki, T. J. Antibiot. 2000, 53, 1397.
Molony, M. G.; Trippier, P. C. Synlett 2002, 1871. (e) Wang, Z.;
Molony, M. G. Tetrahedron Lett. 2002, 43, 9629. (f) Bulger, P. G.;
Moloney, M. G.; Trippier, P. C. Org. Biomol. Chem. 2003, 1, 3726. (g)
Webb, M. R.; Donald, C.; Taylor, R. J. K. Tetrahedron Lett. 2006, 47,
549. (h) Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.;
Franci, X.; Pizzonero, M.; Donald, C.; Taylor, R. J. K. Tetrahedron
2008, 64, 4778. (i) Senapati, B. K.; Gao, L.; Lee, S. I.; Hwang, G.-S.;
Ryu, D. H. Org. Lett. 2010, 12, 5088.
(11) (a) Andrews, M. D.; Brewster, A. G.; Moloney, M. G. Synlett
1996, 612. (b) Papillon, J. N. P.; Taylor, R. J. Org. Lett. 2000, 2, 1987. (c)
Mohapatra, D. K.; Mondal, D.; Gonnade, R. G.; Chorghade, M. S.;
Gurjar, M. K. Tetrahedron Lett. 2006, 47, 6031. (d) Donnhoe, T. J.;
Chiu, J. Y. K.; Thomas, R. E. Org. Lett. 2007, 9, 421. (e) Bennett, N. J.;
Prodger, J. C.; Pattenden, G. Tetrahedron 2007, 63, 6216. (f) Yamada,
T.; Sakaguchi, K.; Shinada, T.; Ohfune, Y.; Soloshonok, V. A. Tetra-
hedron: Asymmetry 2008, 19, 2789. (g) Mondal, D.; Bera, S. Synthesis
2010, 3301.
(7) Manam, R. R.; Teisan, S.; White, D. J.; Nicholson, B.; Grodberg,
J.; Neuteboom, S. T. C.; Lam., K. S.; Mosca, D. A.; Lloyd, G. K.; Potts,
B. C. M. J. Nat. Prod. 2005, 68, 240.
(8) For reviews, see: (a) Shibasaki, M.; Kanai, M.; Fukuda, N.
Chem. Asian J. 2007, 2, 20. (b) Potts, B. C.; Lam, K. S. Mar. Drugs
2010, 8, 835.
(12) (a) Kende, A. S.; Kawamura, K.; DeVita, R. J. J. Am. Chem.
Soc. 1990, 112, 4070. (b) Onyango, E. O.; Tsurumoto, J.; Imai, N.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed.
2007, 46, 6703.
r
10.1021/ol202306d
Published on Web 09/02/2011
2011 American Chemical Society

total synthesis of any other members except neooxazo-
lomycin12 has yet to be accomplished. Herein we report the
first total synthesis of oxazolomycin A (1).
chloride. Upon treatment of 8 with a catalytic amount of
In(OTf)3 in the presence of DBU in boiling toluene, regio-
and stereoselective cyclization took place to afford lactam
9 as the sole product in good yield. It should be stressed
that the reaction occurred with complete E-selectivity and
without epimerization. As previously reported,12b expo-
sure of 9 to OsO4ÀNMO conditions allowed the installa-
tion of three contiguous asymmetric centers including two
quaternary centers in a single operation to give lactone 10,
quantitatively. The ester group of 10 was then chemoselec-
tively reduced via an acid chloride to give alcohol 6.
Scheme 1. Retrosynthesis of Oxazolomycin A
Scheme 2. Synthesis of the Key γ-Lactone16
Taking into account the labile nature of 1 under various
deprotection conditions, we focused on a challenging
strategy wherein the final step is the selective construction
of the β-lactone ring from unprotected tetrahydroxy acid 2
(Scheme 1). Based on the methodology developed in our
synthesis of neooxazolomycin,12b we envisioned the as-
sembly of 2 from the left-hand segment 3, the middle
segment 4, and the right-hand segment 5. For the right-
hand segment 5, we considered an approach from γ-lactam
6, neooxazolomycin’s right-hand core,12b via cleavage of
the γ-lactone, methylation of the secondary alcohol, and
appropriate protection. Compound 6 can be expected to
serve as a common synthetic precursor of most members of
this family of antibiotics. For the left-hand segment 3, we
sought to address the preparation by a method potentially
applicable to other geometrical isomers.
The opening phase of our effort was the development of
an efficient second-generation synthesis of 613 by taking
advantage of an In(III)-catalyzed Conia-ene type cyclization14
which we have recently developed (Scheme 2). Thus, alkynol
7,12b readily available from methyl (S)-3-hydroxy-2-
methylpropionate, was converted to amide 8 by Jones
oxidation followed by condensation with dimethyl 2-
(methylamino)malonate15 via the corresponding acid
After several shorter approaches proved inefficient,17
the key right-hand segment 17 was elaborated as follows
(Scheme 3). Thus, compound 6 was converted to TBS ether
11 in good yield by sequential methoxymethylation,
NaBH4 reduction of the lactone ring, and selective silyla-
tion. The subsequent methylation of 11 was cleanly
achieved using Meerwein reagent and a proton sponge18
to provide 12 in 95% yield. After desilylation of 12, Jones
oxidation followed by Pinnick oxidation and ZrCl4-
mediated cleavage19 of the MOM protecting group
afforded hydroxy acid 14. After many discouraging
results, we eventually found that treatment of 14
with triisopropylsilyloxymethyl(dodecyl)sulfane20 in the
presence of CuBr2, tetrabutylammonium bromide, and
triethylamine allowed the selective esterification without
affecting the primary hydroxy group to give ester 15 in
(17) For example, the compound obtained from 6 by a four-step
sequence (i. i-Pr2Si(OTf)2; ii. DIBAH; iii. NaBH4; iv. Ac2O) did not
undergo methylation.
(18) Fortanet, J. C.; Debergh, J. R.; De Brabander, J. K. Org. Lett.
2005, 7, 685.
(19) Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R.
(13) The early stages of the work were presented at the 17th Interna-
tional Conference on Organic Synthesis (ICOS-17) (Daejeon, Korea,
June 22À27, 2008). Hatakeyama, S. Pure Appl. Chem. 2009, 81, 217.
(14) Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.; Hata-
keyama, S. Angew. Chem., Int. Ed. 2008, 47, 6244.
Tetrahedron Lett. 2004, 45, 9229.
(20) Sawada’s protocol was modified using odorless dodecanethiol in
place of malodorous ethanethiol according to the technique developed
by Node et al. Sawada, D.; Ito, Y. Tetrahedron Lett. 2001, 42, 2501.
Niside, K.; Ohsugi, S.; Miyamoto, T.; Kumar, K.; Node, M. Monatsh.
Chem. 2004, 135, 189.
(15) Heckendorn, R. Helv. Chim. Acta 1990, 73, 1700.
(16) Highly improved in total yield and number of steps compared
with the previous route12b (24% in 14 steps versus 15% in 17 steps).
Org. Lett., Vol. 13, No. 19, 2011
5399

67% overall yield from 12. It turned out that this ester-
ification did not proceed selectively in the absence of
triethylamine to afford the compound in which both the
carboxylic acid and the primary alcohol were protected.
The envisaged right-hand segment 5 was successfully pre-
pared as aldehyde 17 from 15 by a three-step sequence
involving protection as the dioxasilinane, debenzylation,
and Dess-Martin oxidation.
improvement of the procedure12b we previously reported.
The synthesis began with a Cinchona alkaloid-catalyzed
asymmetric cyclocondensation24 of an aldehyde and an acid
chloride. Thus, according to Nelson’s protocol,24c alde-
hyde 20, readily available from propargyl alcohol,12b was
reacted with propionyl chloride using 0.2 equiv of 22 and 4
equiv of LiClO4 at À78 °C to give β-lactone 21 in ex-
cellent enantioselectivity (98% ee) and diastereoselectivity
(>99% de).25,26 After methanolysis of 21, methylation27
of the lithium enolate generated from 23 afforded 24 in
good yield. Desilylation of 24 followed by TBS protection
gave known intermediate 25 which was converted to 26
following the previously established procedure.12b Io-
doalkene 26 was then subjected to Stille coupling with
stannane 2710h using Pd(PPh3)4, CuI, and CsF28 in DMF
at room temperature to give Z,Z,E-triene 28 in geometri-
cally pure form. Whenthiscouplingwascarried out using a
Pd(0) catalyst alone, isomerization of the triene system to
some extent was always observed. Upon successive desily-
lation, saponification, and acetylation of the resulting
hydroxy acid, 28 furnished the left-hand segment 3.
Scheme 3. Synthesis of the Right-Hand Segment
Scheme 5. Synthesis of the Left-Hand Segment29
The middle segment 4 was prepared from allylamine in
three steps in good overall yield (Scheme 4).21 Allylamine
was first converted to 18, which was then subjected to a
cross-metathesis reaction22 with acrolein using a second
generation HoveydaÀGrubbs catalyst followed by Takai’s
iodoalkenylation23 to provide 4 as a 8:1 E/Z-mixture.
Geometrically pure 4 was obtained by recrystallization
from AcOEt.
Scheme 4. Synthesis of the Middle Segment
(24) (a) Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001, 1731. (b)
Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123,
7945. (c) Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126,
5352. (d) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 6358.
(25) Isobutyryl chloride was not effective for the cyclocondensation
reaction with 20, and the desired β-lactone was not obtained at all.
(26) The cyclocondensation reaction with the E-isomer of 20 gave the
corresponding β-lactone in excellent enantio- and diastereoselectivity
(97% ee, >99% de) in 82% yield. The geometrically isomeric left-hand
segments of oxazolomycins B and C were stereoselectively synthesized
from this β-lactone. These syntheses will be reported in due course.
(27) Seebach, D.; Aebi, D.; Wasmuth, D. Org. Synth. 1985, 63, 109.
(28) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Chem.;Eur. J. 2005, 11,
3294.
The left-hand segment 3 was prepared by the method
outlined in Scheme 5 which features a remarkable
(21) Previously, compound 4 was prepared from propargyl alcohol in
18% yield (9 steps). See the Supporting Information of ref 12b.
(22) Cossy, J.; Bouzzouz, S.; Hoveyda, A. H. J. Organomet. Chem.
2001, 634, 216.
(23) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
5400
Org. Lett., Vol. 13, No. 19, 2011

uration and its S-epimer in 81% yield. Dess-Martin oxida-
tion followed by L-selectride reduction afforded 29 and the
7S-epimer in a ratio of 4:1. After separation, the latter was
recycled by the above-mentioned oxidationÀreduction
procedure. As a result of this sequence, 29 was obtained
in ca. 50% yield from 17. After acetylation, treatment of 30
with DBU provided the corresponding free amine which
was directly condensed with the left-hand segment 3 using
BOPCl togive amide 31 in acceptable yield. Exposure of 31
to HF-pyridine followed by saponification allowed us to
obtain the desired tetrahydroxy acid 2 after acidification
with ion-exchange resin. Finally, treatment of 2 with
Scheme 6. Synthesis of Oxazolomycin A
HATU32 in the presence of Hunig’s base in THF at room
€
temperature furnished oxazolomycin A (1) in 40% yield
from 31. The spectroscopic data were identical with
those1a,3,33 reported for natural oxazolomycin A. The struc-
ture of synthetic 1 was further confirmed by the comparison
of the spectral data of its diacetate with those reported.1a,33
In conclusion, we have achieved the first total synthesis
of oxazolomycin A (1) in 34 steps of the longest linear
sequence in 1.4% overall yield from methyl (S)-3-hydroxy-
2-methylpropionate. The convergent methodology is of
general value in approaches to other oxazolomycins, the
synthesis of which is currently under investigation.
Acknowledgment. This work was supported by the
Grant-in-Aid for Scientific Research (A) (22249001) from
JSPS and the Grant-in-Aid for Scientific Research on
Innovative Areas “Reaction Integration”(No. 2105)
(22106538) from MEXT. Wethank Prof. Daisuke Uemura
(Keio University) and Prof. Hiroshi Kanzaki (Okayama
University) forproviding us with valuable information and
copies of 1H and 13C NMR spectra of oxazolomycin A and
its diacetate.
With the three segments in hand, we addressed the total
synthesis of oxazolomycin A (1) through their union,
complete deprotection, and the selective formation of the
β-lactone ring (Scheme 6). The right-hand segment 17 was
first united with the middle segment 4 under NozakiÀ
HiyamaÀKishi reaction conditions30,31 using 6 equiv of
CrCl2 and 0.2 equiv of NiCl2 in THFÀDMSO at room
temperature to give a 3:2 mixture of 29 with a 7R config-
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) Highly improved in total yield and number of steps compared
with the previous route12b (29% in 14 steps versus 12% in 17 steps).
(30) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.;
Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
(31) Panek, J. S.; Liu., P. J. Am. Chem. Soc. 2000, 122, 11090.
(32) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(33) Kawai, S.; Kawabata, G.; Kobayashi, A.; Kawazu, K. Agric.
Biol. Chem. 1989, 53, 1127.
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