Total synthesis of (+/-)-8alpha-hydroxystreptazolone.

Article abstract of DOI:10.1021/ol020189e

[reaction: see text] The intramolecular Pauson-Khand reaction of 2-oxazolone derivatives with a suitable pentynyl appendage exclusively gave the corresponding 4-hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.0(5,11)]undec-5-en-7,10-diones. Based on this newly developed Pauson-Khand reaction of 2-oxazolone-alkyne derivatives, the first total synthesis of (+/-)-8alpha-hydroxystreptazolone was accomplished in a highly stereoselective manner.

Full text of DOI:10.1021/ol020189e

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4301-4304
Total Synthesis of
(±)-8r-Hydroxystreptazolone
Izumi Nomura and Chisato Mukai*
Faculty of Pharmaceutical Sciences, Kanazawa UniVersity, Takara-machi,
Kanazawa 920-0934, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received September 19, 2002
ABSTRACT
The intramolecular Pauson−Khand reaction of 2-oxazolone derivatives with a suitable pentynyl appendage exclusively gave the corresponding
4-hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.05,11]undec-5-en-7,10-diones. Based on this newly developed Pauson−Khand reaction of
2-oxazolone-alkyne derivatives, the first total synthesis of (±)-8r-hydroxystreptazolone was accomplished in a highly stereoselective manner.
Streptazolin (1) was first isolated from cultures of Strepto-
myces Viridochromogenes by Drautz et al. in 1981.1 This
lipophilic neutral tricyclic compound has been shown to
possess antibiotic and antifungal activities.2 Its unique
structural features as well as its promising biological activity
profile have thus far led to four total syntheses.3-6 The total
synthesis of 1 was first reported by Kozikowski and Park3
in a racemic form. Overman and Flann4 completed an
enantioselective synthesis of 1 starting from L-tartrate.
Kibayashi and co-workers5 also reported an enantioselective
Figure 1.
synthesis of 1 starting from L-tartrate by taking advantage
Tang et al.7 very recently reported the isolation of a
streptazolin-dimer and three new streptazolin analogues,
including 8R-hydroxystreptazolone (2)8 together with strepta-
zolin (1) and related known compounds9 as secondary
metabolites from Streptomyces sp. and Viridochromogenes
via chemical screening. As part of our program directed
of a palladium-mediated ring-closure reaction. In addition,
the chiral auxiliary-mediated asymmetric synthesis of 1 was
recently published by Comins and Huang.6
(1) Drautz, H.; Za¨hner, H.; Kupfer, E.; Keller-Schierlein, W. HelV. Chim.
Acta 1981, 64, 1752.
(2) (a) Grabley, S.; Kluge, H.; Hoppe, H.-U. Angew. Chem., Int. Ed.
Engl. 1987, 26, 664. (b) Grabley, S.; Hammann, P.; Kluge, H.; Wink, J.;
Kricke, P.; Zeeck, A. J. Antibiot. 1991, 44, 797. (c) Grabley, S.; Hammann,
P.; Thiericke, R.; Wink, J.; Philipps, S.; Zeeck, A. J. Antibiot. 1993, 46,
343.
(3) (a) Kozikowski, A. P.; Park, P. J. Am. Chem. Soc. 1985, 107, 1763.
(b) Kozikowski, A. P.; Park, P. J. Org. Chem. 1990, 55, 4668.
(4) Flann, C. J.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115.
(5) Yamada, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 1996, 118,
1054.
(6) Huang, S.; Comins, D. L. J. Chem. Soc., Chem. Commun. 2000,
569.
(7) Tang, Y.-Q.; Wunderlich, D.; Sattler, I.; Grabley, S.; Feng, X.-Z.;
Thiericke, R. Abstract of Division of Organic Chemistry, Presented at the
223rd National Meeting of the American Chemical Society, Orlando, FL,
April, 2002; p 341.
(8) Tang et al. called compound 2 8R-hydroxystreptazolone.7 According
to the IUPAC nomenclature system, (()-2 should be described as
(4R*,7R*,8R*,11R*)-6-acetyl-4,7-dihydroxy-9-oxa-1-azatricyclo[6.2.1.05,11]-
undec-5-en-10-one. This numbering system is used for the tricyclic
compounds in this manuscript.
(9) Puder, C.; Loya, S.; Hizi, A.; Zeeck, A. J. Nat. Prod. 2001, 64, 42.
10.1021/ol020189e CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/06/2002

toward the development of stereoselective Pauson-Khand
reactions10 and their application to the total synthesis of
natural products,11 we have given considerable attention to
the total synthesis of streptazolin and its related natural
products via the Pauson-Khand reaction. A general retro-
synthetic analysis for streptazolin and its analogues is
outlined in Scheme 1. A common structural feature of these
azolone-alkyne derivative 12 with the simplest C2-unit, an
ethyl group, at the C6-position8 to not only identify suitable
ring-closing conditions but also determine the level of
stereoselectivity that could be expected in the intramolecular
Pauson-Khand reaction. Thus, the 2-oxazolone-alkyne
derivative 12, required for the intramolecular Pauson-Khand
reaction consistent with our retrosynthesis, was easily pre-
pared from the known alcohol 7 by conventional means, as
shown in Scheme 2. Oxidation of 7 was followed by addition
Scheme 1
Scheme 2a
natural products3-6,9,12 is the 7-hydroxy-6-substituted-9-oxa-
1-azatricyclo[6.2.1.05,11]undecan-10-one framework 3.8 There-
fore, we envisioned that the tricyclic core framework,
namely, 4-hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.05,11]-
undec-5-en-7,10-dione 4,8 would be a useful intermediate
for the synthesis of various streptazolin-related compounds.
The tricyclic skeleton 4 might be directly constructed by the
intramolecular Pauson-Khand reaction of the 2-oxazolone
derivative 5, which has a pentynyl moiety on a nitrogen atom.
To the best of our knowledge, no previous reports have dealt
with 2-oxazolone derivatives as an olefin counterpart in the
Pauson-Khand reaction. Thus, this would be the first
example in which 2-oxazolone is used as an olefin moiety
(an enamine equivalent13) in the Pauson-Khand reaction.
2-Oxazolone-alkyne derivative 5 can be prepared from the
coupling reaction between the iodo derivative 6 and 2-ox-
azolone. This Letter describes our preliminary results regard-
ing (i) the stereoselective construction of the 9-oxa-1-
azatricyclo[6.2.1.05,11]undec-5-en-7,10-dione skeleton based
on the intramolecular Pauson-Khand reaction of 2-ox-
azolone derivatives and (ii) its successful application to the
first total synthesis of (()-8R-hydroxystreptazolone (2).
Since the targeted streptazolin-related natural products
have a C2-unit at the C6-position,8 we prepared the 2-ox-
a Reaction conditions: (a) SO3‚Py, DMSO, Et3N, 0 °C; (b)
nBuLi, TMSCtCH, THF, -78 °C, (75%); (c) K2CO3, MeOH, rt,
(97%); (d) TBDPSCl, imidazole, DMF, rt, (98%); (e) nBuLi, THF,
-78 °C, then EtI, 45 °C; (f) PPTS, MeOH, rt; (g) I2, PPh3, imid-
azole, CH2Cl2, rt, (69%); (h) 2-oxazolone, NaH, DMF, 0 °C, (86%).
of the acetylide, derived from trimethylsilylacetylene, to
afford 8 in 75% yield. The terminal silyl group of 8 was
removed by base treatment to afford 9 (97%), the secondary
hydroxy group of which was then protected with a tert-
butyldiphenylsilyl (TBDPS) group to give 10 in 98% yield.
Introduction of an ethyl group at the triple-bond terminus
of 10 was followed by desilylation and iodination to give
the iodo derivative 11 in 69% overall yield. The coupling
reaction between 11 and 2-oxazolone proceeded, upon
treatment with NaH in DMF, to produce 12 in 86% yield.
The intramolecular Pauson-Khand reaction of 12 was
carried out under various conditions, and typical results are
summarized in Table 1. Treatment of 12 with Co2(CO)8 in
Et2O gave the corresponding cobalt complex, which was then
heated in acetonitrile14 without a promoter to give only a
trace amount of 13 (entry 1). Amine oxides such as
trimethylamine N-oxide (TMANO)15 and N-methylmorpho-
line N-oxide (NMO)16 were found to be effective promoters
for the Pauson-Khand reaction of cobalt-complexed 12
(entries 2-5). In particular, Pe´rez-Castells’ procedure17 using
TMANO and 4 Å molecular sieves in toluene at -10 °C
(10) (a) Mukai, C.; Uchiyama, M.; Sakamoto, S.; Hanaoka, M. Tetra-
hedron Lett. 1995, 36, 5761. (b) Mukai, C.; Kim, J. S.; Uchiyama, M.;
Sakamoto, S. Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1998, 2903. (c)
Mukai, C.; Kim, J. S.; Uchiyama, M.; Hanaoka, M. Tetrahedron Lett. 1998,
39, 7909. (d) Mukai, C.; Kim, J. S.; Sonobe, H.; Hanaoka, M. J. Org. Chem.
1999, 64, 6822. (e) Mukai, C.; Sonobe, H.; Kim, J. S.; Hanaoka, M. J.
Org. Chem. 2000, 65, 6654. (f) Mukai, C.; Nomura, I.; Yamanishi, K.;
Hanaoka, M. Org. Lett. 2002, 4, 1755.
(11) Mukai, C.; Kobayashi, M.; Kim, I. J.; Hanaoka, M. Tetrahedron
2002, 58, 5225.
(12) (a) Cossy, J.; Pe´vet, I.; Meyer, C. Synlett 2000, 122. (b) Cossy, J.;
Pe´vet, I.; Meyer, C. Eur. J. Org. Chem. 2001, 2841.
(13) Very recently, the carbamate and amide functionalities were used
as an enamine equivalent in Pauson-Khand reaction. (a) Magnus, P.;
Fielding, M. R.; Wells, C.; Lynch, V. Tetrahedron Lett. 2002, 43, 947. (b)
Dom´ınguez, G.; Casarrubios, L.; Rodr´ıguez-Noriega, J.; Pe´rez-Castells, J.
HelV. Chim. Acta 2002, 85, 2856.
(14) (a) Hoye, T. R.; Suriano, J. A. J. Org. Chem. 1993, 58, 1659. (b)
Chung, Y. K.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L.
Organometallics 1993, 12, 220.
(15) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett
1991, 204.
(16) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289.
(17) Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez, G.; Pe´rez-Castells,
J. Org. Lett. 1999, 1, 1187.
4302
Org. Lett., Vol. 4, No. 24, 2002

was acetylated under conventional conditions to give 16 in
quantitative yield. NOE experiments20 of 16 clearly showed
that the newly generated stereogenic center (C7-position) was
not the same as that of streptazolin (1) and its related natural
products. Inversion of the configuration at the C7-position
was realized by exposure of 15 to Mitsunobu conditions (p-
nitrobenzoic acid, DEAD, and triphenylphosphine), which
lead to the exclusive formation of 18 with the desired
stereochemistry in 94% yield from 13. p-Nitrobenzoylation
of 15 gave 17, the C7-epimer of 18, in 95% overall yield
from 13. Comparison of the coupling constant21 between H-7
and H-8 in both 17 and 18 with those of streptazolin and its
related compounds, in combination with the results of NOE
experiments20 of 16, unambiguously established that both
17 and 18 have the stereochemistries depicted in Scheme 3.
Table 1. Pauson-Khand Reaction of 12
entry
promoter
heat
solvent
MeCN
time
temp. yield (%)
1
2
3
4
5
6
7
75 min 75 °C
trace
37
TMANO‚2H2O
TMANO‚2H2O
NMO
TMANO/4 Å MS toluene
iPrSMe
CyNH2
CH2Cl2
CH2Cl2
CH2Cl2
3 h
rt
5.5 h
20 h
12 h
reflux
rt
55
38
-10 °C
60
Cl(CH2)2Cl 45 min reflux
Cl(CH2)2Cl 30 min reflux
16
11
Scheme 4a
effected ring-closure of the cobalt-complexed 12, resulting
in the exclusive formation of 13 in 60% yield (entry 5). The
desired product 13 was also obtained, but in lower yields,
under Sugihara conditions18 (entries 6 and7).
Desilylation of 13 followed by acetylation gave 14 in 79%
yield. The relative stereochemistry of the three chiral carbon
centers in 13 and 14 was determined by an examination of
the NMR spectrum19 of 14. We next sought to transform
Scheme 3a
a Reaction conditions: (a) NaH, DMF, 0 °C, (83%); (b) NaH-
MDS, MeCHO, THF, -78 °C (86%); (c) Co2(CO)8, Et2O, rt; (d)
TMANO, 4 Å MS, toluene, -10 °C (51%); (e) MOMCl, iPr2NEt,
CH2Cl2, reflux; (f) NaBH4, CeCl3, MeOH, 0 °C (90%); (g)
p-NO2C6H4CO2H, PPh3, DEAD, benzene, 60 °C; (h) concentrated
HCl, THF, 60 °C; (i) Dess-Martin periodinane, CH2Cl2, rt (65%);
(j) K2CO3, MeOH, rt; (k) TBAF, THF, rt (82%).
a Reaction conditions: (a) TBAF, THF, rt; (b) Ac2O, Et3N,
DMAP, CH2Cl2, 14 (79% from 13), 16 (quantitative from 13); (c)
NaBH4, CeCl3, MeOH, 0 °C; (d) p-NO2C6H4COCl, Et3N, DMAP,
CH2Cl2, 40 °C (95% from 13); (e) p-NO2C6H4CO2H, DEAD, PPh3,
benzene, rt (94% from 13).
the carbonyl functionality of 13 into a hydroxy group with
the desired stereochemistry. Thus, reduction of 13 with
NaBH4 in the presence of CeCl3 gave the alcohol 15, which
We could now develop an efficient procedure for construc-
ting the tricyclic framework of streptazolin and its related
(18) Sugihara, T.; Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2801. (b) Sugihara, T.; Yamada,
M.; Yamaguchi, M.; Nishizawa, M. Synlett 1999, 771.
(19) In a NOE experiment with 14, no enhancement was observed
between H-4 and H-11, while the methylene protons of the ethyl group
were enhanced by 4.2% upon irradiation at H-4.
(20) In a NOE experiment with 16, irradiation of H-8 produced not only
11.4% enhancement of H-7 but also 12.6% enhancement of H-11.
(21) H-7 of 17 appeared at δ 5.89 as a doublet with J ) 4.9 Hz, while
that of 18 resonated at δ 5.80 as a singlet. The smaller coupling constant
(J ) 0 Hz) is in good agreement with that of streptazolin and streptazolin
acetate (J ) 0 Hz).1,5
Org. Lett., Vol. 4, No. 24, 2002
4303

natural products, in which all of the stereogenic centers of
8R-hydroxystreptazolone (2) are constructed in a stereocon-
trolled fashion. Therefore, we next focused on the first total
synthesis of 8R-hydroxystreptazolone (2). The coupling reac-
tion of the iodo derivative 1922 with 2-oxazolone afforded
20 in 83% yield. Treatment of 20 with acetaldehyde in the
presence of NaHMDS gave 21 in 86% yield as a mixture of
two diastereoisomers. Cobalt complexation of 2123 was
followed by the Pauson-Khand reaction under the Pe´rez-
Castells’ conditions17 (TMANO and 4 Å molecular sieves
in toluene at -10 °C) to afford the tricyclic compound 22
in 51% yield. The secondary hydroxy group of 2222 was
protected with the MOM group, and the resulting compound
was reduced with NaBH4 in the presence of CeCl3 to give
23 in 90% yield. Transformation of 2323 into 24 was realized
in 65% overall yield upon consecutive exposure of 23 to
Mitsunobu conditions, demethoxymethylation, and oxidation.
Finally, this total synthesis was completed by removing two
protecting groups from the secondary hydroxy moieties of
24 to give (()-8R-hydroxystreptazolone (2) in 82% yield.
The synthetic racemic 8R-hydroxystreptazolone (2) was
Thus, we have developed a novel and efficient procedure
for constructing 7-hydroxy-6-substituted-9-oxa-1-azatricyclo-
[6.2.1.05,11]undec-5-en-7,10-dione (e.g., 13 and 22) by the
intramolecular Pauson-Khand reaction of 2-oxazolone spe-
cies with the proper alkyne appendages. In addition, by taking
advantage of this new method, we achieved the first total
synthesis of (()-8R-hydroxystreptazolone (2) in a highly
stereoselective manner. Since the tricyclic compound 22 has
the entire carbon framework and suitable functionalities for
further elaborations, it should be a versatile intermediate for
the synthesis of streptazolin and its related natural products.
Studies on the conversion of 22 into other related natural
products are now in progress.
Acknowledgment. The authors thank Drs. Y.-Q. Tang,
D. Wunderlich, I. Sattler, and S. Grabley of the Hans-Kno¨ll
Institute of Natural Products Research, Germany, for gener-
1
ously providing H and 13C NMR spectra of natural 8R-
hydroxystreptazolone.
Supporting Information Available: Experimental pro-
1
identical to the natural compound on the basis of their H
and 13C NMR spectra.
1
cedures for conversion of 19 to 2 and spectral data and H
and 13C NMR spectra for 2, 13, 14, 22, and 24. This material
is available free of charge via the Internet at http://pubs.acs.org.
(22) Compound 19 was prepared from 10 in 99% yield according to the
procedure described for converting 10 into 11.
(23) Used as a mixture of two diastereoisomers.
OL020189E
4304
Org. Lett., Vol. 4, No. 24, 2002