Total synthesis of neooxazolomycin

Article abstract of DOI:10.1002/anie.200702229

Two sides to the story: Neooxazolomycin, a member of the oxazolomycin family of antibiotics, was synthesized in naturally occurring form by a convergent approach. This highly stereoselective strategy consists of a Tamao hydrosilylation, palladium-catalyzed enolate alkenylation, dihydroxylation accompanied by lactonization, and a Nozaki-Hiyama-Kishi reaction to construct the right-hand segment as well as an improved route to the left-hand segment. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200702229

Angewandte
Chemie
DOI: 10.1002/anie.200702229
Natural Products
Total Synthesis of Neooxazolomycin**
Evans Otieno Onyango, Joji Tsurumoto, Naoko Imai, Keisuke Takahashi, Jun Ishihara, and
Susumi Hatakeyama*
Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
Neooxazolomycin and oxazolomycin A, origi-
nally isolated from a strain of Streptomyces by
Uemura and co-workers in 1985,[1] together
with the seven other congeners identified to
date constitute a family of structurally unique
oxazole polyene lactam-lactone antibiotics.
These oxazolomycins were found to exhibit
wide-ranging and potent antibacterial and
antiviral activities as well as in vivo antitumor
activity. Their intriguing molecular architec-
tures and biological activities make these
compounds attractive targets for synthesis.[2,3]
In 1990, Kende et al. disclosed the synthesis of
neooxazolomycin,[4] and this superb achieve-
ment is the first and only total synthesis of any
member of this family; however the stereo-
controlled construction of the right-hand core
has remained an unanswered challenge.
Our synthetic plan for neooxazolomycin
makes a disconnection at the amide linkage to
give the left-hand segment 1 and right-hand
segment 2 (Scheme 1). Since Kende et al. had
already demonstrated an effective method for
the synthesis of 1[4] by a Reformatsky-type
aldol reaction[5] and Stille coupling,[6] the major
challenge in the synthesis resided in the
stereoselective construction of 2. From the
retrosynthetic perspective, we envisioned pyr-
rolidinone 4 as a precursor of 2 with consid-
erably less structural complexity which would
Scheme 1. Retrosynthetic analysis of neooxazolomycin. Bn=benzyl, Fmoc=9-fluorenyl-
methyloxycarbonyl.
lead to 2 through a Nozaki–Hiyama–Kishi
reaction[7] and stereoselective dihydroxylation
with concomitant lactonization. We postulated
that this precursor could be accessed by a palladium-catalyzed
cyclization of amide 5. This approach is particularly appealing
since the three contiguous stereogenic centers including two
quaternary centers could be created by one dihydroxylation
process.
[*] E. O. Onyango, J. Tsurumoto, N. Imai, K. Takahashi, Dr. J. Ishihara,
Prof. Dr. S. Hatakeyama
Graduate School of Biomedical Sciences
Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan)
Fax: (+81)95-819-2426
E-mail: susumi@nagasaki-u.ac.jp
The required amide 5 was synthesized in a completely
stereoselective manner by taking advantage of the intra-
molecular hydrosilylation[8] developed by Tamao et al.[9]
(Scheme 2). Thus, alkynol 8 was first prepared by the coupling
of alkyne 6[10] and triflate 7,[11] both readily available from (S)-
hydroxy-2-methylpropanoate, followed by desilylation. Reac-
tion of 8 with tetramethyldisilazane provided hydrodimethyl-
silyl ether 9, which upon hydrosilylation with [Pt(dvds)][12] as a
catalyst in THF at room temperature followed by exposure of
the resulting siloxane 10 to iodine in the presence of CsF in
[**] We thank Professor Daisuke Uemura (Nagoya University) for the
generous gift of natural neooxazolomycin, and Professor Takanori
Suzuki (Hokkaido University) for the X-ray analysis of the mono-TBS
ether of 12. This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (16073213) from The Ministry of
Education, Culture, Sports, Science, and Technology (MEXT).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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6703

Communications
found to be crucial for the predominant produc-
tion of the E isomer.[13] After Jones oxidation of
11, the resulting carboxylic acid was condensed
with dimethyl 2-(methylamino)malonate[14] via
the corresponding acid chloride to give amide 5.
Treatment of amide 5 with Pd(OAc)2/Ph3P in
the presence of K2CO3 and nBu4NBr in aqueous
DMF at 708C[15] resulted in a clean stereoselec-
tive cyclization to produce pyrrolidinone 4 in
good yield. In the subsequent crucial dihydrox-
ylation of 4, we gratifyingly found that OsO4/
NMO conditions promoted a highly a-face-
selective dihydroxylation accompanied by con-
comitant lactonization to yield lactone 3 as the
sole product; the other stereoisomer was not
detected in this transformation. The observed
high diastereoselectivity can be explained by
assuming that 17 is the preferred conformer,
where the approach of OsO4 is restricted to the
a face. Support for this proposal came from
NOE experiments[16] and molecular mechanics
calculations.[17] After hydrolysis of 3, the result-
ing carboxylic acid was chemoselectively con-
verted into 12 by a Fujisawa reduction.[18] The
configuration of 12 was unambiguously con-
firmed by X-ray analysis of the corresponding
mono-tert-butyldimethylsilyl
(mono-TBS)
ether.[19] After protection of 12 as its dioxasili-
nane, debenzylation and Dess–Martin oxidation
afforded aldehyde 13. After considerable exper-
imentation with various conditions, a Nozaki–
Hiyama–Kishi reaction of 13 with 14[20] was
found to be best achieved[21] using 4 equivalents
of CrCl2 and 0.2 equivalents of NiCl2 in THF/
DMSO at room temperature to give 15 in
satisfying yield. Although no diastereoselectiv-
ity was observed in this reaction, Dess–Martin
oxidation followed by reduction with l-selec-
tride allowed the highly stereoselective produc-
tion of 16 with the desired R configuration.
Exposure of 16 to HF/pyridine followed by
acetylation of the resulting triol furnished the
right-hand segment 2, almost quantitatively.
The left-hand segment 1 was constructed by
the method outlined in Scheme 3, which gave a
remarkable improvement in the overall yield
compared with the procedure used by Kende
et al.[4] Thus, reaction[22] of 2,2-diethoxyethanol
(18) with KSCN under acidic conditions fol-
lowed by butylation of the resulting oxazole-2-
thiol afforded 19 in good yield. Copper-cata-
lyzed propargylation[23] of 19 cleanly produced
20 which, upon desulfurization, desilylation, and
hydrostannylation, gave stannane 22 as a 6:1
mixture of E and Z isomers. It should be noted
that although Stille coupling of 22 with 23[24]
Scheme 2. Synthesis of right-hand segment 2: a) nBuLi, DMPU/THF, À788C; b) TBAF,
THF, 81% (2 steps); c) (HMe2Si)2NH (1.1 equiv), neat; d) [Pt(dvds)] (0.3 mol%), THF;
e) I2 (1 equiv), CsF(1.5 equiv), DMF/MeOH (5:1), 82% (3 steps); f) H 2CrO4, aq
acetone, À108C; g) SOCl2, CH2Cl2; h) 2-(methylamino)malonate, toluene, 08C, 62%
(3 steps); i) Pd(OAc)2 (5 mol%), Ph3P (20 mol%), nBu4NBr (1 equiv), K2CO3 (4 equiv),
DMF/H2O (9:1), 708C, 84%; j) OsO4 (0.4 equiv), NMO (4Àequiv), THF/H2O (3:1),
+
=
88%; k) 4m LiOH, THF, then 1m HCl; l) [Me2N CHCl] Cl , MeCN/THF(1:4), 0 8C,
then NaBH4, DMF, À788C to RT, 57% (3 steps); m) iPr2Si(OTf)2, 2,6-lutidine,
ClCH2CH2Cl, reflux; n) H2, Pd/C, MeOH; o) Dess–Martin periodinane, CH2Cl2, 83%
(3 steps); p) 14 (1.7 equiv), CrCl2 (4 equiv), NiCl2 (0.2 equiv), THF/DMSO (3:1), 73%;
q) Dess–Martin periodinane, CH2Cl2, 87%; r) l-selectride, THF, À788C, 96%; s) 46%
HF/pyridine/H2O/MeCN (1:4:2:20), 08C; t) Ac2O, pyridine, 92% (2 steps).
TBDPS=tert-butyldiphenylsilyl, DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidi-
none, TBAF=tetra-n-butylammonium fluoride, dvds=1,3-divinyl-1,1,3,3-tetramethyldi-
siloxane, NMO=4-methylmorpholine N-oxide, Tf=trifluoromethanesulfonyl.
DMF/MeOH furnished (E)-iodoalkenol 11 with perfect
stereoselectivity in good yield. In the iodination step, the
above-mentioned combination of solvent and additive was
afforded 24 as an inseparable mixture of E and Z isomers, the
left-hand segment 1 could be obtained in geometrically pure
form through recrystallization of 25. Finally, following the
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Chemie
[1]a) T. Mori, K. Takahashi, M. Kashiwabara, D.
Uemura, Tetrahedron Lett. 1985, 26, 1073 –
1076; b) K. Takahashi, M. Kawabata, D.
Uemura, Tetrahedron Lett. 1985, 26, 1077 –
1078.
[2]For a review, see M. G. Moloney, P. C. Trippier,
M. Yaqoob, A. Wang, Curr. Drug Discovery
Technol. 2004, 1, 181 – 199.
[3]a) T. J. Donohoe, J. Y. K. Chiu, R. E. Thomas,
Org. Lett. 2007, 9, 421 – 424; N. J. Bennet, J. C.
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6216 – 6231, and references therein.
[4]A. S. Kende, K. Kawamura, R. J. DeVita, J. Am.
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[5]T. Harada, T. Mukaiyama, Chem. Lett. 1982,
161 – 164.
[6]J. K. Stille, B. L. Groh, J. Am. Chem. Soc. 1987,
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[7]a) H. Jin, J. Uenishi, W. J. Christ, Y. Kishi, J.
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Takai, M. Tagashira, T. Kuroda, K. Oshima, K.
Utimoto, H. Nozaki, J. Am. Chem. Soc. 1986,
108, 6048 – 6050.
[8]For a review, see I. Ojima, Z. Li, J. Zhu in The
Chemistry ofOrganic Silicon Compounds
,
Vol. 2 (Eds.: Z. Rappoport, Y. Apeloig),
Wiley, New York, 1998, pp. 1687 – 1792.
[9]K. Tamao, K. Maeda, T. Tanaka, Y. Ito,
Tetrahedron Lett. 1988, 29, 6955 – 6956.
[10]B. M. Trost, J. P. N. Papillon, J. Am. Chem. Soc.
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[11]A. Abiko, O. Moriya, S. A. Filla, S. Masamune,
Angew. Chem. 1995, 107 869 – 871; Angew.
Chem. Int. Ed. Engl. 1995, 34, 793 – 795.
[12]S. E. Denmark, W. Pan, Org. Lett. 2001, 3, 61 –
64.
Scheme 3. Completion of the total synthesis of neooxazolomycin: a) KSCN, conc. HCl,
MeCN, reflux; b) KH, nBuI, THF, 79% (2 steps); c) tBuLi, CuCN·2 LiCl, THF, À788C,
then BrCH2CCSiMe3, À788C to RT, 94%; d) Raney Ni, acetone/EtOH (1:1), reflux, 92%;
e) AgOTf, CH2Cl2/MeOH/H2O (7:4:1), 73%; f) nBu3SnH, AIBN, 708C, 88%; g) [PdCl2-
(MeCN)2] (3 mol%), DMF, 79%; h) 47% HF/MeCN, then recrystallization; i) LiOH,
THF/MeOH/H2O (3:1:1); j) Ac2O, pyridine, then sat. NaHCO3, aq MeOH, 80%
(3 steps); k) 2, DBU, CH2Cl2, add to the mixed anhydride (1, BOPCl, Et3N, CH2Cl2),
60%; l) LiOH (10 equiv), THF/H2O (3:1), then 1m HCl, 59%. AIBN=2,2’-azobisisobu-
tyronitrile, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, BOPCl=bis(2-oxo-3-oxazolidinyl)-
phosphinic chloride.
[13]When the iodination of 10 was carried out using
I2 (1 equiv) and AgNO3 (1 equiv) in EtOH at
room temperature, the corresponding Z isomer
was obtained exclusively in 50% yield.
previous synthetic route,[4] condensation of 1 with the free
[14]R. Heckendorn, Helv. Chim. Acta 1990, 73, 1700 – 1718.
[15]X. Liu, J. R. Deschamp, J. M. Cook, Org. Lett. 2002, 4, 3339 –
3342.
[16]The NOESY spectrum was recorded in [D 8]THF/D2O (3:1),
which was the same solvent system as that employed for the
osmylation.
[17]Conformer 17 was suggested to be the energetically most stable
by Molecular mechanics calculations (MMFF, Macro Model
8.5).
[18]T. Fujisawa, T. Mori, T. Sato, Chem. Lett. 1983, 835 – 838.
[19]CCDC-643979 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
amine generated in situ from 2 followed by deacetylation of
26 furnished neooxazolomycin, which was identical with a
natural specimen by spectroscopic (1H and 13C NMR) and
chromatographic (TLC and HPLC) comparisons.
In conclusion, neooxazolomycin has been synthesized by a
convergent strategy that features a highly stereoselective
approach involving Tamao hydrosilylation, palladium-cata-
lyzed enolate alkenylation, dihydroxylation accompanied by
lactonization, and a Nozaki–Hiyama–Kishi reaction to con-
struct the right-hand segment 2 and an improved assembly of
the left-hand segment 1. Application of this methodology to
the synthesis of other oxazolomycins is currently under
investigation.
[20]Prepared by Takai–Utimoto olefination of ( E)-4-(Fmoc)amino-
but-2-enal; see the Supporting Information and also K. Takai, K.
Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108, 7408 – 7410.
[21]J. S. Panek, P. Liu, J. Am. Chem. Soc. 2000, 122, 11090 – 11097.
[22]Y. Watanabe, WO 2003006422.
Received: May 21, 2007
Published online: July 31, 2007
[23]a) C. M. Shafer, T. F. Molinsky, J. Org. Chem. 1998, 63, 551 – 555;
b) J. P. Marino, H. N. Nguyen, Tetrahedron Lett. 2003, 44, 7395 –
7398.
[24]Prepared by a modified Kende procedure, where the method for
the preparation of (Z)-2-methyl-5-(trimethylsilyl)pent-2-en-4-
ynal, required for the key aldol reaction, was highly improved;
see the Supporting Information.
Keywords: alkaloids · antibiotics · natural products ·
total synthesis
.
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