Studies on the Total Synthesis of Streptazolin and Its Related Natural Products: First Total Synthesis of (±)-8α-Hydroxystreptazolone

Article abstract of DOI:10.1021/jo0356816

The intramolecular Pauson-Khand reaction of 2-oxazolone derivatives with a suitable heptynyl appendage gave exclusively the corresponding 4-hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.0 ^5,11]-undec-5-ene-7,10-diones. On the basis of this newly developed Pauson-Khand reaction of 2-oxazolone-alkyne derivatives, the first total synthesis of (±)-8α-hydroxystreptazolone was accomplished in a highly stereoselective manner. In addition, (±)-7-epi-8α -hydroxystreptazolone was also synthesized.

Full text of DOI:10.1021/jo0356816

Stu d ies on th e Tota l Syn th esis of Str ep ta zolin a n d Its Rela ted
Na tu r a l P r od u cts: F ir st Tota l Syn th esis of
(()-8r-Hyd r oxystr ep ta zolon e
Izumi Nomura and Chisato Mukai*
Faculty of Pharmaceutical Sciences, Kanazawa University,
Takara-machi 13-1, Kanazawa 920-0934, J apan
cmukai@kenroku.kanazawa-u.ac.jp
Received November 15, 2003
The intramolecular Pauson-Khand reaction of 2-oxazolone derivatives with a suitable heptynyl
appendage gave exclusively the corresponding 4-hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.05,11]-
undec-5-ene-7,10-diones. On the basis of this newly developed Pauson-Khand reaction of 2-ox-
azolone-alkyne derivatives, the first total synthesis of (()-8R-hydroxystreptazolone was accomplished
in a highly stereoselective manner. In addition, (()-7-epi-8R-hydroxystreptazolone was also
synthesized.
In tr od u ction
total synthesis of 1 was first reported by Kozikowski and
Park6 in racemic form through the intramolecular nitrile
oxide [2 + 3]-cycloaddition for construction of the azabi-
cyclo[4.3.0] framework. Overman and Flann7 completed
the first enantioselective synthesis of 1 starting from
L-tartrate via a ring-closing reaction between the N-
acyliminium cation and the vinylsilane species for con-
struction of the azabicyclo[4.3.0] framework. Kibayashi
and co-workers8 also reported an enantioselective syn-
thesis of 1 starting from L-tartrate by taking advantage
of a palladium-mediated ring-closure reaction. Comins
and Huang9 recently revealed an asymmetric synthesis
of 1 based on a chiral auxiliary-mediated asymmetric
preparation of the dihydropyridone derivative, followed
by palladium-mediated construction of the tricyclic frame-
work. All these syntheses of streptazolin (1) used a
stepwise procedure for the construction of the 9-oxa-1-
azatricyclo[6.2.1.05,11]undecan-10-one skeleton (Figure 1).
Streptazolin (1) was first isolated from a culture of
Streptomyces viridochromogenes by Drautz et al. in 1981.1
This lipophilic neutral tricyclic compound has been shown
to possess antibiotic and antifungal activities.2 Tang et
al.3 recently reported the isolation of some of the novel
and more oxidized streptazolin-related natural products,
8R-hydroxystreptazolone (2),4 4,12-epoxystreptazoline
(3),4 and 9â-hydroxystreptazoline (4).4 In addition to
these, the streptazolin dimer (5)4 together with strepta-
zolin (1) and related known compounds5 as secondary
metabolites from Streptomyces sp. and S. viridochromo-
genes were isolated, all via chemical screening. Because
of its unique structural features as well as its promising
biological activity profile, the first-isolated streptazolin
(1), having the common basic skeleton of the streptazolin
analogues, has been synthesized by four groups.6-9 The
As part of our study on the total synthesis of natural
products based on the Pauson-Khand reaction,10 we have
devoted considerable attention to the total synthesis of
streptazolin and its related natural products. A general
retrosynthetic analysis for streptazolin and its analogues
is outlined in Scheme 1. A common structural feature of
these natural products1-3,5-9,11 is the 7-hydroxy-6-substi-
tuted-9-oxa-1-azatricyclo[6.2.1.05,11]undecan-10-one frame-
work 6.4 Therefore, we envisioned the tricyclic core
framework, namely 4-hydroxy-6-(C2-unit)-9-oxa-1-aza-
tricyclo[6.2.1.05,11]undec-5-ene-7,10-dione 7,4 being the
key intermediate for further elaboration leading to the
* To whom correspondence should be addressed. Tel: +81-76-234-
4411. Fax: +81-76-234-4410.
(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) Tang, Y.-Q.; Wunderlich, D.; Sattler, I.; Grabley, S.; Feng, X.-
Z.; Thiericke, R. Abstract of Division of Organic Chemistry. 223rd ACS
National Meeting, Apr 7-12, Orlando; American Chemical Society:
Washington, DC, 2002; p 341.
(4) Tang et al. called compound 2 8R-hydroxystreptazolone, com-
pound 3 4,12-epoxystreptazolin, compound 4 9â-hydroxystreptazolin,
and compound 5 streptazolin dimer.3 According to the IUPAC nomen-
clature 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.
(8) Yamada, H.; Aoyagi, S.; Kibayashi, C. J . Am. Chem. Soc. 1996,
118, 1054.
(9) Huang, S.; Comins, D. L. J . Chem. Soc., Chem. Commun. 2000,
569.
(10) Mukai, C.; Kobayashi, M.; Kim, I. J .; Hanaoka, M. Tetrahedron
2002, 58, 5225.
(11) (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.
(5) Puder, C.; Loya, S.; Hizi, A.; Zeeck, A. J . Nat. Prod. 2001, 64,
42.
(6) (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.
(7) Flann, C. J .; Overman, L. E. J . Am. Chem. Soc. 1987, 109, 6115.
10.1021/jo0356816 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004
J . Org. Chem. 2004, 69, 1803-1812
1803

Nomura and Mukai
SCHEME 2a
a
Reaction conditions: (a) SO3‚Py, DMSO, Et3N, CH2Cl2, 0°C;
(b) nBuLi, TMSCtCH, THF, -78°C (75%); (c) K2CO3, MeOH, rt
(97%); (d) TBDPSCl, imid, DMF, rt, (98%); (e) nBuLi, THF, -35°C,
then EtI, 45°C; (f) PPTS, MeOH, rt; (g) I2, PPh3, imid, CH2Cl2, rt
(69%); (h) 2-oxazolone, NaH, DMF, 0°C (86%).
F IGURE 1. Streptazolin and its related natural products.
SCHEME 1
Resu lts a n d Discu ssion
In t r a m olecu la r P a u son -Kh a n d R ea ct ion of 2-
Oxa zolon e Der iva tives. Since the targeted streptazo-
lin-related natural products have a C2-unit at the
C6-position,4 we first prepared the 2-oxazolone-alkyne
derivative 15 with the simplest C2-unit, an ethyl group,
at the triple bond terminus to not only identify suitable
ring-closing conditions, but also to determine the level
of stereoselectivity that could be expected in the intramo-
lecular Pauson-Khand reaction. Thus, the 2-oxazolone-
alkyne derivative 15, required for the intramolecular
Pauson-Khand reaction of our retrosynthesis, was easily
prepared from the known alcohol 10 by conventional
means, as shown in Scheme 2. Oxidation of 10 was
followed by addition of the acetylide derived from tri-
methylsilylacetylene to afford 11 in 75% yield. The
terminal silyl group of 11 was removed by base treatment
to afford 12,14 the secondary hydroxyl group of which was
protected with a tert-butyldiphenylsilyl (TBDPS) group
to give 13 in 98% yield. Introduction of an ethyl group
at the triple bond terminus of 13 was followed by
desilylation and iodination to furnish the iodo derivative
14 in 69% overall yield. The coupling reaction between
14 and 2-oxazolone proceeded, upon treatment with NaH
in DMF, to produce 15 in 86% yield.
We began the intramolecular Pauson-Khand reaction
of the 2-oxazolone derivative by treating 15 with Co2(CO)8
in Et2O at room temperature to give the corresponding
cobalt complex, which was heated in acetonitrile15 with-
out a promoter to give only a trace amount of 16. When
the cobalt complex was exposed to trimethylamine N-
oxide dihydrate (TMANO‚2H2O, 3.5 equiv)16 in THF at
room temperature for 3 h, the desired tricyclic compound
16 was obtained in 37% yield as the sole isolable product
(Scheme 3). The relative stereochemistry of 16 was
determined by 1H NMR spectral considerations. Com-
pound 16 was converted into the acetate derivative 17
synthesis of various streptazolin-related natural prod-
ucts. The tricyclic skeleton 7 might be directly con-
structed by the intramolecular Pauson-Khand reaction
of the 2-oxazolone derivative 8 which has a suitable
heptynyl moiety on the nitrogen atom. To the best of our
knowledge, no previous reports have dealt with 2-ox-
azolone derivatives as the olefin counterpart in the
Pauson-Khand reaction. Thus, this would be the first
example in which a 2-oxazolone was used as the olefin
moiety (an enamine equivalent12) in the Pauson-Khand
reaction. During these ongoing studies, Magnus12a and
Pe´rez-Castells12b independently reported examples of the
Pauson-Khand reaction of an enamine equivalent. The
2-oxazolone-alkyne derivative 8, a substrate for the
Pauson-Khand reaction, can be prepared from the
coupling reaction between the heptynyl iodo derivative
9 and 2-oxazolone.
On the basis of the above simple retrosynthetic analy-
sis, (()-8R-hydroxystreptazolone (2)3,4 was chosen as our
first target natural product in this investigation. In this
paper, we describe in detail the results13 relating (i) the
development of the stereoselective and direct construction
of the 9-oxa-1-azatricyclo[6.2.1.05,11]undec-5-ene-7,10-di-
one skeleton (e.g., 7) via the intramolecular Pauson-
Khand reaction of 2-oxazolone derivatives and (ii) its
successful application to the first total synthesis of (()-
8R-hydroxystreptazolone (2).
(14) (a) Takano, S.; Sugihara, T.; Ogasawara, K. Tetrahedron Lett.
1991, 32, 2797. (b) Pearson, W. H.; Postich, M. J . J . Org. Chem. 1994,
59, 5662.
(15) (a) Hoye, T. R.; Suriano, J . A. J . Org. Chem. 1993, 58, 1659. (b)
Chung, Y. K.; Lee, B. Y.; J eong, N.; Hudecek, M.; Pauson, P. L.
Organometallics 1993, 12, 220.
(12) Very recently, the carbamate and amide functionalities were
used as enamine equivalents in the 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.
(13) Part of this work was published as a preliminary communica-
tion: Nomura, I.; Mukai, C. Org. Lett. 2002, 4, 4301.
(16) J eong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett
1991, 204.
1804 J . Org. Chem., Vol. 69, No. 6, 2004

Total Synthesis of (()-8R-Hydroxystreptazolone
SCHEME 4a
F IGURE 2. Proposed mechanism for Pauson-Khand reac-
tion.
a
Reaction conditions: (a) NaBH4, CeCl3, MeOH, 0 °C (quant);
(b)Ac2O, Et3N, DMAP, CH2Cl2, rt (99%from 16);(c)p-NO2C6H4COCl,
Et3N, DMAP, CH2Cl2, 40 °C (95% from 16); (d) p-NO2C6H4CO2H,
DEAD, PPh3, benzene, rt (94% from 16).
SCHEME 3
could occur. This would not be the case in the intermedi-
ate 18 where the siloxy group and the C2-substituent
(ethyl group) have a trans alignment. As a result, the
cyclization pathway via the intermediate 18 would be
preferred over that via 19.
We next sought to transform the carbonyl functionality
of the tricyclic compound 16 into a hydroxyl group with
the same relative stereochemistry as that of the target
natural products (Scheme 4). Thus, reduction of 16 with
NaBH4 in the presence of CeCl3 gave the alcohol 21 in a
quantitative yield, which was then acetylated under
conventional conditions to provide 22 in 99% yield. In
the NOE study of 22, irradiation of H-8 produced a 11.4%
enhancement of H-7 as well as a 12.6% enhancement of
H-11, clearly showing that the newly generated stereo-
genic center (C7-position) was not the same as that of
streptazolin (1) and its related natural products. Inver-
sion of the configuration at the C7-position was realized
by exposure of 21 to Mitsunobu conditions (p-nitrobenzoic
acid, diethyl azodicarboxylate (DEAD), and triphenylphos-
phine), which led to the exclusive formation of 24 with
the inverted stereochemistry at the C7-position in 96%
in 79% yield by treatment with tetra-n-butylammonium
fluoride (TBAF) and then acetic anhydride. The NOE
study of 17 showed no enhancement between H-4 and
H-11, whereas the methylene protons of the C6-ethyl
group were enhanced by 4.2% upon irradiation at H-4.
This observation was in good accord with the prediction
based on analysis of the molecular model.
Although the chemical yield (37%) of 16 was not
satisfactory, we could synthesize stereoselectively the
desired tricyclic product 16, having the core common
framework of the target natural products, from the
2-oxazolone-alkyne derivative 15 in a straightforward
manner. The mechanism for the stereoselective formation
of 16 is uncertain, but it might be tentatively rationalized
on the basis of the mechanistic hypothesis proposed by
Magnus (Figure 2).17 Two plausible cobalt-metallocyclic
intermediates 18 and 19, derived from the cobalt-com-
plexed 15, would collapse to the desired 16 and its C4-
epimer 20. In the cobalt-metallocycle 19 leading to 20,
the bulky siloxy group at the C4-position would have a
nonbonding interaction with the C2-carbon appendage
(ethyl group) at the triple bond terminus due to a kind
of 1,3-pseudodiaxial relationship on the sterically con-
gested concave face of the transient cobaltabicyclic
structure; therefore, a serious unfavorable interaction
1
yield. H-7 of 24 appeared at δ 5.80 as a singlet in its H
NMR spectrum, while the 1H NMR spectrum of the
corresponding p-nitrobenzoate derivative 23, derived
from 21 by acylation, revealed H-7 at δ 5.89 as a doublet
(J ) 4.9 Hz). It has been shown that H-7 of streptazolin
1
(1) and its acetate resonate as singlets in their H NMR
spectra.1,8 Thus, comparison of the coupling constant
between H-7 and H-8 in both 23 and 24 with those of
the related natural products, in combination with the
results of the NOE experiments of 22, unambiguously
established that both 23 and 24 have the stereochemis-
tries depicted in Scheme 4.
We could now develop a procedure for constructing the
tricyclic framework of streptazolin and its related natural
products, in which all of the stereogenic centers of 8R-
hydroxystreptazolone (2) are constructed in a stereocon-
trolled fashion. Prior to turning our efforts to the total
synthesis of the target natural product, the most signifi-
cant issue remaining to be solved at this point was to
optimize the ring-closing conditions for the conversion of
(17) (a) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851.
(b) Magnus, P.; Exon, C.; Albaugh-Robertson, P. Tetrahedron 1985,
41, 5861.
J . Org. Chem, Vol. 69, No. 6, 2004 1805

Nomura and Mukai
TABLE 1. P a u son -Kh a n d Rea ction of 2-Oxa zolon e
TABLE 2. P a u son -Kh a n d Rea ction of 2-Oxa zolon e
Der iva tive 15
Der iva tive 25a
a
Reaction conditions: (a) TBAF, THF, rt (98%); (b) Ac2O,
CH2Cl2, rt (94% from 15); (c) TBDMSCl, imid, DMF, 50 °C (86%
from 15); (d) TIPSCl, imid, DMF, 50°C (85% from 15).
to that obtained with TMANO‚2H2O in THF. Sugihara’s
method19 of using amines or sulfides as the promoter did
not improve the yield of 16 (entries 4 to 6). However, the
procedure developed by Pe´rez-Castells20 was found to be
effective for our purposes. Thus, the cobalt-complexed
2-oxazolone derivative15 was exposed to anhydrous
TMANO (4.5 equiv) and 4 Å molecular sieves in toluene
at -10 °C for 12 h to furnish 16 in 60% yield (entry 7).
This transformation was reproducible, and 16 was con-
sistently obtained in the designated yield. We have
developed an efficient method for the construction of
4-hydroxy-6-(C2-unit)-9-oxa-1-azatricyclo[6.2.1.05,11]undec-
5-ene-7,10-dione (e.g., 7 in Scheme 1), a possible common
synthetic intermediate for streptazolin and its related
natural products, in a highly stereoselective manner
based on the intramolecular Pauson-Khand reaction of
the 2-oxazolone derivative in acceptable yields.
Tota l Syn th esis of (()-8R-Hyd r oxystr ep ta zolon e.
As shown in Figure 1, the target natural product, 8R-
hydroxystreptazolone (2), has an acetyl group at the C6-
position.4 Therefore, the 2-oxazolone derivative 29 pos-
sessing a vinyl group at the triple bond terminus was
chosen as the starting material21 because a vinyl group
is well-known to be easily converted to an acetyl group
under the Wacker oxidation conditions (Scheme 5).22 The
2-oxazolone-enyne derivative 29 was prepared from 13
via 27and 28 by conventional means. Exposure of 29 to
ring-closing condition, optimized in Table 2 (entry 7),20
the 2-oxazolone derivative 15 into the tricyclic compound
16. The first effort was directed toward determining the
influence of the protecting group on the secondary
hydroxyl group at the propargyl position in the Pauson-
Khand reaction. Compound 15 was desilylated with
TBAF to give the hydroxyl derivative 25a (98%), which
was subsequently protected with three different protect-
ing groups to afford 25b, 25c, and 25d , respectively. With
four newly synthesized precursors for the Pauson-Khand
reaction in hand, we next investigated the ring-closing
reaction of these compounds under the conditions de-
scribed for the preparation of 16 (Scheme 3). The results
are summarized in Table 1. The hydroxyl derivative 25a
and the TIPS-protected compound 25c provided the
corresponding cyclized products in 20% and 29% yields,
respectively (entries 1 and 4). However, both yields were
lower than that of 16 (37%). Thus, no improvement was
achieved by changing the protecting group on the hy-
droxyl functionality. On the basis of the observation in
Table 1 and the result of the reaction of 15, it might be
concluded that a bulky protection group would be favor-
able in this transformation. Interestingly, it took some-
what longer (20 h) to consume the starting material when
the acetyl congener 25b was submitted to the standard
conditions, presumably due to the electron-withdrawing
nature of the acetoxy group at the propargyl position
(entry 2).
We next screened various Pauson-Khand conditions
by using compound 15. Table 2 summarizes several
typical results. The Pauson-Khand reaction of 15 with
TMANO‚2H2O (3.5 equiv)16 in refluxing CH2Cl2 instead
of THF at room temperature gave a lower yield (23%,
entry 1). Increasing of the amount of TMANO‚2H2O to
4.5 equiv in refluxing CH2Cl2 afforded 16 in an improved
yield of 55% (entry 2). Another N-oxide promoter, N-
methylmorpholine N-oxide (NMO)18 in CH2Cl2 at room
temperature, produced 16 in 38% yield (entry 3), similar
(19) 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.
(20) Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez, G.; Pe´rez-
Castells, J . Org. Lett. 1999, 1, 1187.
(21) The Pauson-Khand reaction of the 2-oxazolone-alkyne deriva-
tive, possessing an acetyl group at the triple bond terminus was not
investigated, because it appeared difficult to differentiate the resulting
two carbonyl functionalities (the C6-acetyl group and the C7-carbonyl
moiety) of the tricyclic compound.
(22) For example, see: (a) Smidt, J .; Hafner, W.; J ira, R.; Sieber,
R.; Sedlmeier, J .; Sabel, A. Angew. Chem. 1962, 74, 93. (b) Tsuji, J .
Synthesis, 1984, 369-384. (c) Molander, G. A.; Cameron, K. O. J . Am.
Chem. Soc. 1993, 115, 830, and references therein.
(18) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289.
1806 J . Org. Chem., Vol. 69, No. 6, 2004

Total Synthesis of (()-8R-Hydroxystreptazolone
SCHEME 5a
SCHEME 6a
a
Reaction conditions: (a) PPTS, MeOH, rt; (b) I2, PPh3, imid,
CH2Cl2, rt (99%); (c) 2-oxazolone, NaH, DMF, 0 °C (83%); (d) vinyl
i
bromide, PdCl2(PPh3)2, CuI, Pr2NH, THF, rt (87%); (e) Co2(CO)8,
Et2O, rt; (f) TMANO, 4 Å MS, toluene, -10 °C (50%); (g) NaBH4,
CeCl3, MeOH, 0 °C (quant); (h) p-NO2C6H4CO2H, DEAD, PPh3,
benzene, rt (93%).
a
Reaction conditions: (a) NaHMDS, CH3CHO, THF, -78 °C
(83%); (b) Co2(CO)8, Et2O, rt; (c) TMANO, 4 Å MS, toluene, -10
°C (51%); (d) TBDMSCl, imid, DMF, 70 °C; (e) NaBH4, CeCl3,
MeOH, 0 °C (78%); (f) p-NO2C6H4CO2H, DEAD, PPh3, benzene,
rt; (g) 10% HCl, MeOH, rt; (h) Dess-Martin periodinane, CH2Cl2,
rt (80%); (i) K2CO3, MeOH, rt; (j) TBAF, THF, rt (82%).
produced the desired tricyclic compound 30 in 50% yield
in a highly stereoselective manner. According to the
procedure described for the transformation of 16 to 24,
compound 32 was obtained in high yield from the keto
derivative 30 by stereoselective reduction followed by the
Mitsunobu reaction. However, it soon became apparent
that 32 could not provide the acetyl derivative 33 having
all the required functionalities for the synthesis of 2
under the Wacker conditions, but gave instead an in-
temperature. Although substrate 36 for the inversion
reaction was used as a mixture of two diastereoisomers,
the isolated 36 and the inverted product 37 were both
apparently a single stereoisomer, the stereochemistries
of which were undetermined. This result obviously
indicated that one of two diastereoisomers of 36 reacted
readily with the Mitsunobu reagents to provide the
desired 37, while the other isomer was inactive toward
those reagents. The chemical yield of 37 (45%) was not
good enough; nevertheless, we took this compound for-
ward to the final stage of the synthesis of 2. Removal of
the TBDMS group of 37 under acidic conditions gave the
corresponding hydroxyl derivative, which was then oxi-
dized with Dess-Martin periodinane to afford 38 in 80%
yield. Finally successive treatment of 38 with potassium
carbonate and TBAF produced (()-8R-hydroxystrepta-
zolone (2) in 82% yield. The synthetic racemic 8R-
hydroxystreptazolone (2) was identical to the natural
compound based on a comparison of their 1H and 13C
NMR spectra.
The first total synthesis of (()-2 from 2-oxazolone was
thus accomplished. One-half of the synthetic intermediate
36, however, could not be converted into2. This step
might have made this total synthesis less efficient.
Therefore, an alternative procedure was necessary to
transform 36 into 37. One of two diastereoisomers of 36
did not react with the Mitsunobu reagent which might
indicate steric congestion by the bulky TBDMS group,
although this was unclear. We envisioned constructing
an essential acetyl functionality at the C6-position prior
to inverting the stereochemistry at the C7-position. Thus,
compound 36 was converted into the corresponding acetyl
derivative 40 as shown in Scheme 7. Treatment of 40
with the Mitsunobu reagents under various conditions,
1
tractable mixture.22 A careful inspection of the H NMR
spectrum of the crude mixture disclosed the following
observations: (i) disappearance of vinyl protons, (ii) no
peaks due to the acetyl group, and (iii) lower field-shifted
proton presumably due to an aldehyde functionality.
J udging from this observation, we tentatively concluded
that oxidative carbon-carbon bond cleavage of the vinyl
group must have occurred, although no pure compounds
could be isolated from the reaction mixture.
We next addressed the introduction of the 1-hydroxy-
ethyl group as an acetyl precursor at the triple bond
terminus of the 2-oxazolone derivative.21 Treatment of
28 with acetaldehyde in the presence of sodium hexa-
methyldisilazide (NaHMDS) afforded 34 in 83% yield as
a mixture of two diastereoisomers, which were exposed
to Co2(CO)8 under the Pauson-Khand conditions to
produce the corresponding tricyclic compound 35 in 51%
yield (Scheme 6). Protection of the secondary hydroxyl
moiety of 35 with the TBDMS group was followed by
stereoselective reduction of the carbonyl functionality to
furnish 36 in 78% yield. According to our model studies
(transformation of 21 to 24 in Scheme 4), inversion of
the C7-hydroxyl group of 36 (a mixture of two diastere-
oisomers) was carried out under Mitsunobu conditions
at room temperature to give the inverted product 37 in
45% yield along with 50% yield of the recovered starting
material 36. Complete consumption of the starting mate-
rial 36 could not be achieved even at higher reaction
J . Org. Chem, Vol. 69, No. 6, 2004 1807

Nomura and Mukai
SCHEME 7a
was followed by stereoselective reduction to give 42 in
90% yield. The Mitsunobu reaction of 42, which required
60 °C for completion of the reaction,24 afforded the
inverted products, which were subsequently exposed to
concentrated HCl and Dess-Martin periodinane to pro-
duce 38 in 65% overall yield. Thus, the transformation
of 36 into 37 was improved by changing the protecting
group on the secondary hydroxyl moiety.
In summary, 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-ene-7,10-diones (e.g., 16,
31, and 35) by the intramolecular Pauson-Khand reaction
of the 2-oxazolone species with the required alkyne
appendages. In addition, by taking advantage of this
newly developed method, we have achieved the first total
synthesis of (()-8R-hydroxystreptazolone (2) in a highly
stereoselective manner. Synthesis of (()-7-epi-8R-hydrox-
ystreptazolone (41)4 was also achieved. Since the tricyclic
compound 35 has the entire carbon framework and
suitable functionalities for further elaborations, it should
be a versatile intermediate for the synthesis of strepta-
zolin and its related natural products. Studies on the
conversion of 35 into other related natural products are
now in progress.
a
Reaction conditions: (a) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C; 10%
HCl, MeOH, rt; (c) Dess-Martin periodinane, CH2Cl2, rt (50%);
(d) K2CO3, MeOH, rt (96%); (e) TBAF, THF, rt (83%).
Exp er im en ta l Section
SCHEME 8 a
5-(ter t-Bu tyld im eth ylsiloxy)-1-tr im eth ylsilyl-1-p en tyn -
3-ol (11). To a solution of 10 (4.75 g, 25.0 mmol), DMSO (5.30
mL, 75.0 mmol), and Et3N (10.4 mL, 75.0 mmol) in dry
CH2Cl2 (100 mL) was added SO3‚pyridine (11.9 g, 75.0 mmol)
at 0 °C. After being stirred for 1 h, the reaction mixture was
quenched by addition of water and extracted with CH2Cl2. The
extract was washed with water and brine, dried, and concen-
trated to afford the crude aldehyde. To a solution of trimeth-
ylsilylacetylene (5.30 mL, 37.5 mmol) in dry THF (100 mL)
was added nBuLi in hexane (1.43 M, 21.0 mL, 29.7 mmol) at
-78 °C. After being stirred for 1 h, a solution of the crude
aldehyde in THF (20 mL) was added to the reaction mixture,
which was then stirred for 3 h. The reaction mixture was
quenched by addition of water and extracted with AcOEt. The
extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was chromatographed with
hexane-AcOEt (15:1) to afford 11 (5.36 g, 75%) as a pale
yellow oil: IR 3600, 3455, 2170 cm-1 1H NMR δ 4.66-4.53
;
a
Reaction conditions: (a) MOMCl, iPr2NEt, CH2Cl2, reflux; (b)
NaBH4, CeCl3, MeOH, 0 °C (90%); (c) p-NO2C6H4CO2H, PPh3,
DEAD, benzene, 60 °C; (d) concd HCl, THF, 60 °C; (e) Dess-Martin
periodinane, CH2Cl2, rt (65%).
(m, 1H), 4.10-3.98 (m, 1H), 3.89-3.76 (m, 1H), 3.44-3.30 (m,
1H), 2.07-1.78 (m, 2H), 0.90 (s, 9H), 0.17 (s, 9H), 0.09 (s, 3H),
0.08 (s, 3H); 13C NMR δ 106.2, 89.2, 62.2, 61.0, 38.4, 25.8,
18.13, -0.1, -5.6, -5.6; FABMS m/z 287 (M+ + 1, 1.9); HRMS
calcd for C14H30O2Si2 286.1784, found 286.1778.
however, led to the recovery of the starting material 40.23
The intramolecular hydrogen bonding between the C6-
acetyl carbonyl oxygen and the C7-hydroxyl group pre-
sumably caused farily low reactivity toward the Mitsuno-
bu reagents. It should be mentioned here that desilylation
of 40 with TBAF afforded (()-7-epi-8R-hydroxystrepta-
zolone (41)4 in 83% yield, although its isolation has not
been reported.
On the basis of these results, we decided to change the
protecting group on the secondary hydroxyl group of the
tricyclic compound, such as 37 in Scheme 6, from the
bulky TBDMS group to the less sterically hindered
methoxymethyl (MOM) group (Scheme 8). Protection of
the hydroxyl group of the tricyclic compound 35, obtained
from the Pauson-Khand reaction, with the MOM group
5-(t er t -Bu t yld im e t h ylsiloxy)-3-(t er t -b u t yld ip h e n yl-
siloxy)-1-p en tyn e (13). To a solution of 11 (660 mg, 2.30
mmol) in MeOH (20 mL) was added K2CO3 (410 mg, 3.00
mmol) at room temperature. The reaction mixture was stirred
for 2 h, and MeOH was evaporated off. The residue was diluted
with water and extracted with AcOEt. The extract was washed
with water and brine, dried, and concentrated to dryness. The
residue was chromatographed with hexane-AcOEt (30:1) to
afford the known 1214 (480 mg, 97%) as a colorless oil: IR 3467,
3307 cm-1; 1H NMR δ 4.68-4.55 (m, 1H), 4.12-4.00 (m, 1H),
3.89-3.78 (m, 1H), 3.50 (brs, 1H), 2.46 (d, 1H, J ) 2.0 Hz),
2.08-1.80 (m, 2H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13
C
NMR δ 84.4, 72,8, 61.7, 61.0, 38.3, 25.8, 18.1, -5.6. To a
solution of 12 (480 mg, 2.23 mmol) in dry DMF (0.8 mL) were
added imidazole (297 mg, 4.36 mmol) and TBDPSCl (0.87 mL,
3.27 mmol) at room temperature. After being stirred for 5 h,
the reaction mixture was quenched by addition of water and
(23) In some cases, a trace amount of the inverted compound could
be detected.
(24) The reaction did not occur at room temperature.
1808 J . Org. Chem., Vol. 69, No. 6, 2004

Total Synthesis of (()-8R-Hydroxystreptazolone
extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was
chromatographed with hexane-AcOEt (30:1) to afford 13 (1.00
g, 99%) as a colorless oil: IR 3307 cm-1; 1H NMR δ 7.78-7.64
(m, 4H), 7.47-7.30 (m, 6H), 4.54 (dt, 1H, J ) 6.6, 2.0 Hz), 3.74
(t, 2H, J ) 6.6 Hz), 2.28 (d, 1H, J ) 2.0 Hz), 2.05-1.80 (m,
2H), 1.08 (s, 9H), 0.81 (s, 9H), -0.02 (s, 3H), -0.03 (s, 3H);
13C NMR δ 136.0, 135.8, 133.5, 133.4, 129.7, 129.6, 127.6,
127.4, 84.7, 73.0, 61.1, 59.2, 41.4, 26.9, 25.9, 19.3, 18.2, -5.4,
-5.4; MS m/z 452 (M+, 0.1); FABHRMS calcd for C27H41O2Si2
453.2645, found 453.2650. Anal. Calcd for C27H40O2Si2: C,
71.62; H, 8.90. Found: C, 71.47; H, 8.84.
evaporated off, and the residue was passed through a short
pad of silica gel with hexane-AcOEt (5:1) to afford the crude
cobalt complex. To a solution of the crude cobalt complex in
dry THF was added TMANO‚2H2O (37.4 mg, 0.33 mmol) at
room temperature. After being stirred for 3 h, the reaction
mixture was passed through
a short pad of Celite and
concentrated to dryness. The residual oil was chromatographed
with hexane-AcOEt (5:1) to afford 16 (16.0 mg, 37%) as a
colorless oil: IR 1759, 1726, 1652 cm-1; 1H NMR δ 7.69-7.31
(m, 10H), 4.98 (dd, 1H, J ) 3.4, 2.0 Hz), 4.88 (d, 1H, J ) 6.4
Hz), 4.54 (d, 1H, J ) 6.4 Hz), 3.85-3.71 (m, 2H), 1.98-1.83
(m, 2H), 1.71-1.58 (m, 2H), 1.11 (s, 9H), 0.76 (t, 3H, J ) 7.3
Hz); 13C NMR δ 199.6, 165.9, 156.0, 137.9, 135.5, 132.4, 130.4,
128.1, 127.9, 71.4, 64.7, 55.2, 37.5, 36.7, 26.9, 19.3, 16.1, 12.3;
MS m/z 461 (M+, 2.7); HRMS calcd for C27H31NO4Si 461.2023,
found 461.2021. Anal. Calcd for C27H31NO4Si: C, 70.25; H,
6.77; N, 3.03. Found: C, 70.27; H, 7.12; N, 2.91.
Rin g Closu r e of 15 w ith TMANO a n d 4 Å MS in
Tolu en e (Ta ble 2, En tr y 7). To a solution of 15 (63.4 mg,
0.15 mmol) in Et2O (10 mL) was added Co2(CO)8 (74.9 mg, 0.22
mmol) at room temperature. After being stirred for 1 h, Et2O
was evaporated off, and the residue was passed through a
short pad of silica gel with hexane-AcOEt (5:1) to afford the
crude cobalt complex. To a solution of the crude cobalt complex
and 4 Å MS (507 mg) in dry toluene (2.0 mL) was added
TMANO (50.0 mg, 0.67 mmol) at -10 °C. After being stirred
at -10 °C for 12 h, the reaction mixture was passed through
a short pad of Celite and concentrated to dryness. The residual
oil was chromatographed with hexane-AcOEt (5:1) to afford
16 (40.2 mg, 60%).
(4R *,7R *,8R *,11R *)-4-Ace t oxy-6-e t h yl-9-oxa -1-a za -
tr icyclo[6.2.1.05,11]u n d ec-5-en e-7,10-d ion e (17). To a solu-
tion of 16 (55.0 mg, 0.12 mmol) in dry THF (1.5 mL) was added
TBAF (1.00 M solution in THF, 0.14 mL, 0.14 mmol) at room
temperature. After being stirred for 30 min, THF was evapo-
rated off, and the residue was passed through a short pad of
silica gel with hexane-AcOEt (1:2) to afford the crude alcohol.
To a solution of the crude alcohol and DMAP (1.00 mg, 0.08 ×
10-1 mmol) in dry CH2Cl2 (1.5 mL) were added Et3N (0.03
mmol, 0.21 mmol) and Ac2O (0.02 mL, 0.21 mmol) at 0 °C.
After being stirred for 2 h, CH2Cl2 was evaporated off, and
the residue was chromatographed with hexane-AcOEt (2:1)
to afford 17 (24.9 mg, 79%) as colorless needles: mp 133-134
°C (hexane-AcOEt); IR 1761, 1731, 1654 cm-1; 1H NMR δ 5.85
(t, 1H, J ) 2.9 Hz), 4.65 (d, 1H, J ) 6.4 Hz), 4.57 (d, 1H, J )
6.4 Hz), 3.85 (ddd, 1H, J ) 14.2, 5.9, 1.0 Hz), 3.54 (ddd, 1H, J
) 14.2, 12.7, 3.4 Hz), 2.34 (q, 2H, J ) 7.3 Hz), 2.17-2.10 (m,
1H), 2.14 (s, 3H), 1.96-1.86 (m, 1H), 1.05 (t, 3H, J ) 7.3 Hz);
13C NMR δ 199.0, 169.7, 161.0, 155.8, 141.1, 71.4, 65.4, 55.1,
37.5, 33.0, 20.7, 16.4, 12.5. MS m/z 265 (M+, 3.3); HRMS calcd
for C13H15NO5 265.0951, found 265.0951. Anal. Calcd for
5-(ter t-Bu tyld ip h en ylsiloxy)-7-iod o-3-h ep tyn e (14). To
a solution of 13 (2.50 g, 5.53 mmol) in dry THF (50.0 mL) was
added nBuLi (1.23 M hexane solution, 9.0 mL, 11.0 mmol) at
-35 °C. After the mixture was stirred for 30 min, ethyl iodide
(1.80 mL, 22.0 mmol) was added, and the mixture was
gradually warmed to 45 °C. The reaction mixture was stirred
for 4 h at the same temperature. The reaction mixture was
quenched by addition of saturated aqueous NH4Cl and ex-
tracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. To a solution of the
crude product in MeOH (50 mL) was added PPTS (138 mg,
0.55 mmol) at room temperature. After being stirred for 10 h,
MeOH was evaporated off, and the residue was diluted with
water and extracted with AcOEt. The extract was washed with
water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (10:1) to afford crude alcohol. To a solution of
the crude alcohol in dry CH2Cl2 (50.0 mL) were added PPh3
(1.47 g, 5.60 mmol) and imidazole (381 mg, 5.60 mmol) at room
temperature. I2 (1.42 g, 5.60 mmol) was then added to the
reaction mixture, which was stirred for 3 h at room temper-
ature. CH2Cl2 was evaporated off, and the residue was chro-
matographed with hexane-AcOEt (10:1) to afford 14 (1.80 g,
69%) as a colorless oil: 1H NMR δ 7.79-7.66 (m, 4H), 7.48-
7.32 (m, 6H), 4.42 (tt, 1H, J ) 5.9, 2.0 Hz), 3.33-3.22 (m, 2H),
2.23-2.12 (m, 2H), 2.00 (qd, 2H, J ) 7.6, 2.0 Hz), 1.07 (s, 9H),
0.94 (t, 3H, J ) 7.6 Hz); 13C NMR δ 136.0, 135.9, 133.8, 133.4,
129.7, 129.5, 127.6, 127.3, 87.9, 79.2, 64.3, 42.4, 26.9, 19.3, 13.4,
12.3, 1.0; FABMS m/z 477 (M+ + 1, 0.75); FABHRMS calcd
for C23H30IOSi 477.1111, found 477.1103. Anal. Calcd for
C
23H29IOSi: C, 57.98; H, 6.13. Found: C, 58.26; H, 6.21.
3-[(3-ter t-Bu tyld ip h en ylsiloxy)-4-h ep tyn yl]-2-oxa zolo-
n e (15). To a solution of 2-oxazolone25 (20.4 mg, 0.24 mmol)
in dry DMF (3.0 mL) was added NaH (14.0 mg, 0.35 mmol) at
0 °C. After being stirred for 30 min, a solution of 14 (76.0 mg,
0.16 mmol) in DMF (2.0 mL) was added to the reaction
mixture, which was stirred at room temperature for 12 h. The
reaction mixture was quenched by addition of saturated
aqueous NH4Cl and extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated to
dryness. The residue was chromatographed with hexane-
AcOEt (4:1) to afford 15 (59.4 mg, 86%) as a colorless oil: IR
1747 cm-1; 1H NMR δ 7.82-7.63 (m, 4H), 7.50-7.32 (m, 6H),
6.70 (d, 1H, J ) 2.0 Hz), 6.36 (d, 1H, J ) 2.0 Hz), 4.41 (tt, 1H,
J ) 5.6, 2.0 Hz), 3.74 (t, 2H, J ) 7.3 Hz), 2.11-1.90 (m, 4H),
1.08 (s, 9H), 0.98 (t, 3H, J ) 7.6 Hz); 13C NMR δ 155.5, 136.0,
135.7, 133.5, 133.3, 129.9, 129.6, 127.7, 127.4, 127.2, 116.0,
88.2, 79.1, 61.5, 40.4, 37.0, 26.9, 19.2, 13.4, 12.3; MS m/z 433
(M+, 0.36); FABHRMS calcd for C26H32NO3Si 434.2151, found
434.2146. Anal. Calcd for C26H31NO3Si: C, 72.02; H, 7.21; N,
3.23. Found: C, 71.84; H, 7.26; N, 3.19.
C
13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C, 58.72; H,
5.75; N, 5.11.
(4R*,7S*,8R*,11R*)-4-(ter t-Bu tyldiph en ylsiloxy)-6-eth yl-
7-h yd r oxy-9-oxa -1-a za t r icyclo[6.2.1.05,11]u n d ec-5-en -10-
on e (21). To a solution of 16 (4.6 mg, 0.01 mmol) in MeOH
(0.50 mL) were added CeCl3 (3.7 mg, 0.15 × 10-1 mmol) and
NaBH4 (1.0 mg, 0.26 × 10-1 mmol) at 0 °C. After being stirred
for 30 min, MeOH was evaporated off, and the residue was
chromatographed with hexane-AcOEt (3:1) to afford 21 (4.60
mg, 100%) as colorless oil: IR 3566, 1750 cm-1 1H NMR δ
;
7.68-7.61 (m, 2H), 7.59-7.53 (m, 2H), 7.49-7.32 (m, 6H),
4.85-4.77 (m, 2H), 4.73 (t, 1H, J ) 2.9 Hz), 4.69 (d, 1H, J )
5.9 Hz), 3.74-3.63 (m, 2H), 2.38-2.30 (m, 1H), 1.78 (q, 2H, J
) 7.3 Hz), 1.74-1.68 (m, 1H), 1.62-1.54 (m, 1H), 1.07 (s, 9H),
0.80 (t, 3H, J ) 7.3 Hz); 13C NMR δ 157.8, 138.7, 135.6, 133.3,
133.2, 130.0, 129.9, 127.8, 127.6, 78.4, 74.1, 64.1, 61.2, 38.4,
35.3, 26.9, 19.3, 17.9, 12.0; MS m/z 463 (M+, 0.88); HRMS calcd
for C27H33NO4Si 463.2179, found 463.2174.
(4R*,8R*,11R*)-4-(ter t-Bu tyld ip h en ylsiloxy)-6-eth yl-9-
oxa -1-a za tr icyclo[6.2.1.05,11]u n d ec-5-en e-7,10-d ion e (16).
To a solution of 15 (40.7 mg, 0.94 × 10-1 mmol) in Et2O (10
mL) was added Co2(CO)8 (48.1 mg, 0.14 mmol) at room
temperature. After the mixture was stirred for 1 h, Et2O was
(25) (a) Scholz, K. H.; Heine, H. G.; Hartmann, W. J ustus Liebigs
Ann. Chem. 1976, 1319. (b) Kunieda, T.; Abe, Y.; Iitaka, Y.; Hirobe,
M. J . Org. Chem. 1982, 47, 4291. (c) Ho, G.-J .; Mathre, D. J . J . Org.
Chem. 1995, 60, 2271.
(4R*,7S*,8R*,11R*)-7-Acetoxy-4-(ter t-bu tyld ip h en ylsi-
loxy)-6-eth yl-9-oxa -1-a za tr icyclo[6.2.1.05,11]u n d ec-5-en -10-
on e (22). Compound 16 (18.7 mg, 0.04 mmol) was first
J . Org. Chem, Vol. 69, No. 6, 2004 1809

Nomura and Mukai
converted into 21. To a solution of crude 21 and DMAP (1.00
mg, 0.08 × 10-1 mmol) in dry CH2Cl2 were added Ac2O (0.02
mL, 0.21 mmol) and Et3N (0.03 mL, 0.21 mmol) at room
temperature. After being stirred for 2 h, CH2Cl2 was evapo-
rated off, and the residue was chromatographed with hexane-
AcOEt (4:1) to afford 22 (20.0 mg, 99%) as colorless needles:
as a colorless oil: IR 3595, 3447, 1747 cm-1; 1H NMR δ 7.78-
7.62 (m, 4H), 7.49-7.33 (m, 6H), 6.72 (d, 1H, J ) 2.0 Hz), 6.38
(d, 1H × 50/100, J ) 2.0 Hz), 6.37 (d, 1H × 50/100, J ) 2.0
Hz), 4.50-4.39 (m, 1H), 4.37-4.21 (m, 1H), 3.89-3.65 (m, 2H),
2.09-1.93 (m, 3H), 1.23 (d, 3H, J ) 6.6 Hz), 1.07 (s, 9H); 13C
NMR δ 155.5, 135.9, 135.7, 133.3, 133.2, 132.9, 132.8, 129.9,
129.7, 127.7, 127.4, 127.4, 115.8, 88.4, 83.0, 82.9, 61.1, 57.7,
40.2, 36.5, 26.8, 23.7, 23.6, 19.1; FABMS m/z 450 (M+ + 1,
1
mp 135-136 °C (hexane-AcOEt); IR 1744 cm-1; H NMR δ
7.68-7.62 (m, 2H), 7.59-7.54 (m, 2H), 7.49-7.33 (m, 6H), 5.59
(d, 1H, J ) 4.9 Hz), 5.04 (dd, 1H, J ) 6.4, 4.9 Hz), 4.76 (t, 1H,
J ) 2.9 Hz), 4.72 (d, 1H, J ) 6.4 Hz), 3.77-3.63 (m, 2H), 2.11
(s, 3H), 1.79-1.68 (m, 3H), 1.64-1.54 (m, 1H), 1.08 (s, 9H),
0.72 (t, 3H, J ) 7.3 Hz); 13C NMR δ 170.6, 157.9, 136.1, 135.6,
134.3, 133.2, 130.1, 130.0, 127.9, 127.7, 79.6, 72.6, 64.0, 61.4,
2.2); FABHRMS calcd for
C26H32NO4Si 450.2101, found
450.2100. Anal. Calcd for C26H31NO4Si: C, 69.45; H, 6.95; N,
3.12. Found: C, 69.07; H, 7.11; N, 3.06.
(4R*,8R*,11R*,1′R*)- a n d (4R*,8R*,11R*,1′S*)-4-(ter t-
B u t y ld i p h e n y ls i lo x y )-6-(1′-h y d r o x y e t h y l)-9-o x a -1-
a za tr icyclo[6.2.1.05,11]u n d ec-5-en e-7,10-d ion e (35). Accord-
ing to the Pauson-Khand conditions with TMANO and 4 Å
MS in toluene (Table 2, entry 7), 34 (65.0 mg, 0.14 mmol) was
converted into 35 (34.9 mg, 51%) as colorless needles: mp
172.5-173.5 °C (hexane-AcOEt); IR 3564, 3447, 1759, 1720,
1649 cm-1; 1H NMR δ 7.74-7.32 (m, 10H), 5.48 (dd, 1H × 40/
100, J ) 3.6, 1.7 Hz), 5.30 (dd, 1H × 60/100, J ) 3.6, 1.7 Hz),
4.95 (d, 1H, J ) 6.3 Hz), 4.56 (d, 1H, J ) 6.3 Hz), 4.33-4.18
(m, 1H), 3.88-3.67 (m, 2H), 2.05-1.63 (m, 2H), 1.14-1.06 (m,
3H), 1.12 (s, 9H); 13C NMR δ 199.5, 199.0, 167.3, 167.0, 155.8,
138.3, 138.0, 135.6, 132.9, 132.5, 132.3, 130.4, 130.4, 128.0,
127.9, 127.8, 71.4, 64.6, 63.4, 63.2, 55.1, 55.0, 37.2, 36.7, 36.3,
26.9, 26.7, 22.3, 21.8, 19.3; FABMS m/z 478 (M+ + 1, 19).
FABHRMS calcd for C27H32NO5Si 478.2050, found 478.2087.
Anal. Calcd for C27H31NO5Si: C, 67.90; H, 6.54; N, 2.93.
Found: C, 67.62; H, 6.63; N, 2.85.
38.2, 35.3, 26.9, 20.5, 19.3, 18.0, 12.0; FABMS m/z 506 (M+
+
1, 2.0); HRMS calcd for C29H35NO5Si 505.2284, found 505.2278.
Anal. Calcd for C29H35NO5Si: C, 68.88; H, 6.98; N, 2.77.
Found: C, 68.90; H, 7.18; N, 2.77.
(4R*,7S*,8R*,11R*)-4-(ter t-Bu tyldiph en ylsiloxy)-6-eth yl-
7-(p-n itr oben zoyloxy)-9-oxa-1-azatr icyclo[6.2.1.05,11]u n dec-
5-en -10-on e (23). Compound 16 (14.4 mg, 0.03 mmol) was first
converted into 21. To a solution of crude 21 and DMAP (1.00
mg, 0.008 mmol) in dry CH2Cl2 were added p-nitrobenzoyl
chloride (8.40 mg, 0.45 × 10-1 mmol) and Et3N (0.03 mL, 0.2
1 mmol). After being stirred for 3 h, CH2Cl2 was evaporated
off, and the residue was chromatographed with hexane-AcOEt
(4:1) to afford 23 (18.2 mg, 96%) as pale yellow needles: mp
136-137 °C (hexane-AcOEt); IR 1751, 1732 cm-1; 1H NMR δ
8.30-8.24 (m, 2H), 8.22-8.17 (m, 2H), 7.70-7.64 (m, 2H),
7.62-7.57 (m, 2H), 7.51-7.35 (m, 6H), 5.89 (d, 1H, J ) 4.9
Hz), 5.17 (dd, 1H, J ) 6.4, 4.9 Hz), 4.82 (t, 1H, J ) 2.9 Hz),
4.81 (d, 1H, J ) 6.4 Hz), 3.80-3.66 (m, 2H), 1.88-1.74 (m,
3H), 1.70-1.61 (m, 1H), 1.10 (s, 9H), 0.78 (t, 3H, J ) 7.3 Hz);
13C NMR δ 164.3, 157.7, 150.7, 137.1, 135.6, 134.7, 133.6,
133.1, 133.0, 131.0, 130.2, 130.1, 127.9, 127.7, 123.6, 80.9, 72.5,
64.0, 61.5, 38.2, 35.3, 26.9, 19.3, 18.2, 12.2; MS m/z 612 (M+,
0.7); HRMS calcd for C34H36N2O7Si 612.2292, found 612.2285.
Anal. Calcd for C34H36N2O7Si: C, 66.65; H, 5.92; N, 4.57.
Found: C, 66.66; H, 6.15; N, 4.52.
(4R*,7S*,8R*,11R*,1′R*)- a n d (4R*,7S*,8R*,11R*,1′S*)-
6-[1′-(ter t-Bu tyld im eth ylsiloxy)eth yl]-4-(ter t-bu tyld ip h e-
n ylsiloxy)-7-h ydr oxy-9-oxa-1-azatr icyclo[6.2.1.05,11]u n dec-
5-en -10-on e (36). To a solution of 35 (23.0 mg, 0.48 × 10-1
mmol) in dry DMF (0.02 mL) were added TBDMSCl (24.0 mg,
0.16 mmol) and imidazole (11 mg, 0.16 mmol). The reaction
mixture was stirred at 70 °C for 1 h, quenched by addition of
water, and extracted with AcOEt. The extract was washed
with water and brine, dried, and concentrated to dryness. To
a solution of the crude product in MeOH (2.0 mL) were added
NaBH4 (2.20 mg, 0.58 × 10-1 mmol) and CeCl3 (16.0 mg, 0.64
× 10-1 mmol) at 0 °C. The reaction mixture was stirred for 30
min, and MeOH was evaporated off. The reaction mixture was
quenched by addition of water, dried, and concentrated to
dryness. The residue was chromatographed with hexane-
AcOEt (3:1) to afford 36 (22.0 mg, 78%) as a colorless oil: IR
(4R*,7R*,8R*,11R*)-4-(ter t-Bu tyldiph en ylsiloxy)-6-eth yl-
7-(p-n itr oben zoyloxy)-9-oxa-1-azatr icyclo[6.2.1.05,11]u n dec-
5-en -10-on e (24). Compound 16 (23.0 mg, 0.05 mmol) was first
converted into 21. To a solution of crude 21 in dry benzene
(0.04 mL) were added PPh3 (39.0 mg, 0.15 mmol) and p-
nitrobenzoic acid (25.0 mg, 0.15 mmol) at room temperature.
DEAD (23.0 µL, 0.15 mmol) was added to the reaction mixture,
which was then stirred for 4 h at room temperature. Benzene
was evaporated off, and the residue was chromatographed with
hexane-AcOEt (4:1) to afford 24 (29.0 mg, 94%) as colorless
1
3560, 3487, 1751 cm-1; H NMR δ 7.70-7.30 (m, 10H), 5.36
(t, 1H × 50/100, J ) 2.6 Hz), 5.05 (dd, 1H × 50/100, J ) 7.3,
4.6 Hz), 4.88-4.74 (m, 4H × 50/100), 4.67 (t, 1H × 50/100, J
) 2.6 Hz), 4.62 (d, 1H × 50/100, J ) 6.3 Hz), 4.48 (q, 1H ×
50/100, J ) 6.6 Hz), 4.07 (q, 1H × 50/100, J ) 6.3 Hz), 3.82-
3.58 (m, 2H), 3.47 (d, 1H × 50/100, J ) 7.3 Hz), 2.51 (m, 1H
× 50/100), 1.81-1.64 (m, 2H), 1.10-1.03 (m, 3H × 50/100),
1.08 (s, 9H × 50/100), 1.06 (s, 9H × 50/100), 1.01 (d, 3H ×
50/100, J ) 6.3 Hz), 0.76 (s, 9H × 50/100), 0.69 (s, 9H × 50/
100), -0.10 (s, 3H × 50/100), -0.11 (s, 3H × 50/100), -0.15
(s, 3H × 50/100), -0.18 (s, 3H × 50/100); 13C NMR δ 158.4,
157.7, 140.0, 136.3, 135.7, 135.6, 135.6, 134.3, 134.2, 133.4,
133.1, 133.0, 130.2, 130.1, 130.0, 129.8, 127.9, 127.8, 127.8,
127.6, 78.3, 75.0, 73.8, 65.7, 64.4, 64.1, 63.8, 61.2, 61.0, 38.2,
38.1, 35.0, 34.9, 27.0, 26.9, 25.7, 25.6, 23.3, 21.1, 19.4, 19.2,
17.9, 17.6, -4.7, -5.0, -5.1; FABMS m/z 594 (M+ + 1, 18);
FABHRMS calcd for C33H48NO5Si2 594.3071, found 594.3046.
Anal. Calcd for C33H47NO5Si2: C, 66.74; H, 7.98; N, 2.36.
Found: C, 66.36; H, 8.09; N, 2.35.
needles: mp 151.5-152.5 °C (hexane-AcOEt); IR 1751 cm-1
;
1H NMR δ 8.40-8.31 (m, 2H), 8.23-8.14 (m, 2H), 7.75-7.58
(m, 4H), 7.52-7.27 (m, 6H), 5.80 (s, 1H), 5.03 (d, 1H, J ) 6.3
Hz), 4.85-4.75 (m, 1H), 4.80 (d, 1H, J ) 6.3 Hz), 3.88-3.60
(m, 2H), 1.96-1.80 (m, 1H), 1.77-1.40 (m, 3H), 1.11 (s, 9H),
0.80 (t, 3H, J ) 7.6 Hz); 13C NMR δ 163.7, 156.8, 150.8, 141.1,
135.6, 135.6, 134.8, 133.1, 133.0, 130.8, 130.1, 129.9, 127.9,
127.7, 123.7, 84.1, 77.3, 64.3, 61.7, 37.9, 35.3, 26.9, 19.3, 18.5,
12.2; FABMS m/z 613 (M+ + 1, 19); FABHRMS calcd for
C
C
34H36N2O7Si 613.2370, found 613.2365. Anal. Calcd for
34H36N2O7Si: C, 66.65; H, 5.92; N, 4.57. Found: C, 66.68; H,
6.13; N, 4.48.
3-[3-(ter t-Bu tyld ip h en ylsiloxy)-6-h yd r oxy-4-h ep tyn yl]-
2-oxa zolon e (34). To a solution of 28 (175 mg, 0.43 mmol) in
dry THF (5.0 mL) was added NaHMDS (1.00 M solution in
THF, 0.86 mL, 0.86 mmol) at -78 °C. After the mixture was
stirred for 30 min, acetaldehyde (0.20 mL, 3.60 mmol) was
added, and the mixture was then warmed to room temperature
over a period of 2 h. The reaction mixture was quenched by
addition of saturated aqueous NH4Cl and extracted with
AcOEt. The extract was washed with water and brine, dried,
and concentrated to dryness. The residue was chromato-
graphed with hexane-AcOEt (2:1) to afford 34 (165 mg, 86%)
(4R*,7R*,8R*,11R*)-6-[1′-(ter t-Bu t yld im et h ylsiloxy)-
eth yl]-4-(ter t-bu tyldiph en ylsiloxy)-7-(p-n itr oben zoyloxy)-
9-oxa -1-a za tr icyclo[6.2.1.05,11]u n d ec-5-en -10-on e (37). To
a solution of 36 (20.5 mg, 0.04 mmol) in dry benzene (0.08 mL)
were added PPh3 (27.2 mg, 0.10 mmol) and p-NO2C6H4CO2H
(17.4 mg, 0.10 mmol) at room temperature. DEAD (0.02 mL,
0.13 mmol) was then added to the reaction mixture, which was
stirred at 70 °C for 2 h. The reaction mixture was directly
1810 J . Org. Chem., Vol. 69, No. 6, 2004

Total Synthesis of (()-8R-Hydroxystreptazolone
chromatographed with hexane-AcOEt (5:1) to afford 37 (11.6
mg, 45%) and recovered starting material 36 (10.2 mg, 50%)
as a single isomer: Compound 37 was colorless needles:, mp
104-105 °C (hexane-AcOEt); IR 1755, 1734 cm-1; 1H NMR δ
8.36-8.30 (m, 2H), 8.21-8.15 (m, 2H), 7.71-7.62 (m, 4H),
7.49-7.32 (m, 6H), 5.91 (s, 1H), 5.20 (dd, 1H, J ) 3.4, 2.0 Hz),
5.13 (d, 1H, J ) 5.9 Hz), 4.75 (d, 1H, J ) 5.9 Hz), 4.34 (q, 1H,
J ) 6.4 Hz), 3.83-3.62 (m, 2H), 1.79-1.72 (m, 1H), 1.60-1.50
(m, 1H), 1.13 (s, 9H), 0.94 (d, 3H, J ) 6.4 Hz), 0.63 (s, 9H),
-0.13 (s, 3H), -0.23 (s, 3H); 13C NMR δ 163.4, 156.8, 150.8,
142.7, 135.7, 135.6, 135.0, 134.9, 133.2, 133.0, 130.9, 130.2,
130.0, 127.9, 127.7, 123.6, 84.1, 77.3, 65.7, 64.6, 62.3, 37.9, 34.9,
27.0, 25.5, 24.7, 19.5, 17.7, -4.8, -5.2; FABMS m/z 743 (M+
+ 1, 1.8); FABHRMS calcd for C40H51N2O8Si2 743.7184, found
743.7196. Anal. Calcd for C40H50N2O8Si2: C, 64.66; H, 6.78;
N, 3.77. Found: C, 64.75; H, 6.96; N, 3.68; Recovered starting
material 36 was a colorless oil: IR 3483, 1751 cm-1; 1H NMR
δ 7.67-7.34 (m, 10H), 5.05 (dd, 1H, J ) 7.3, 4.4 Hz), 4.79 (dd,
1H, J ) 6.4, 4.4 Hz), 4.68 (t, 1H, J ) 2.5 Hz), 4.62 (d, 1H, J )
6.4 Hz), 4.08 (q, 1H, J ) 6.4 Hz), 3.74 (ddd, 1H, J ) 13.7, 5.4,
1.5 Hz), 3.65 (td, 1H, J ) 13.7, 2.9 Hz), 3.44 (d, 1H, J ) 7.3
Hz), 1.79-1.63 (m, 2H), 1.07 (s, 9H), 1.04 (d, 3H, J ) 6.4 Hz),
0.77 (s, 9H), -0.11 (s, 3H), -0.17 (s, 3H); 13C NMR δ 158.4,
136.3, 135.6, 134.2, 133.1, 133.0, 130.2, 130.1, 127.9, 127.8,
78.3, 75.0, 64.1, 63.8, 61.0, 38.1, 34.9, 26.9, 25.6, 21.1, 19.3,
17.6, -4.7, -5.1; FABMS m/z 594 (M+ + 1, 9.0); FABHRMS
calcd for C33H48NO5Si2 594.3071, found 594.3079. Anal. Calcd
for C33H47NO5Si2: C, 66.74; H, 7.98; N, 2.36. Found: C, 66.40;
H, 8.11; N, 2.35.
63.0, 61.6, 37.3, 34.2, 30.2; 13C NMR (CD3OD) δ 199.7, 159.1,
154.0, 134.8, 81.7, 81.6, 63.5, 63.1, 38.3, 35.7, 30.2; MS m/z
239 (M+, 6.3); HRMS calcd for C11H13NO5 239.0794, found
239.0796.
(4R*,7S*,8R*,11R*)-7-Acet oxy-6-a cet yl-4-(ter t-b u t yl-
d ip h en ylsiloxy)-9-oxa -1-a za t r icyclo[6.2.1.05,11]u n d ec-5-
en -10-on e (39). To a solution of 36 (45.0 mg, 0.76 × 10-1
mmol) in dry CH2Cl2 (2.0 mL) were added DMAP (1.00 mg,
0.08 × 10-1 mmol) and Et3N (0.03 mL, 0.21 mmol) at 0 °C.
Ac2O (0.02 mL, 0.21 mmol) was then added to the reaction
mixture. After being stirred for 2 h, the reaction mixture was
quenched by addition of water and extracted with AcOEt. The
extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad
of silica gel with hexane-AcOEt (4:1) to afford the crude
acetate. To a solution of the crude acetate in MeOH (2.0 mL)
was added 10% HCl (0.06 mL) at room temperature. The
reaction mixture was stirred for 12 h at room temperature,
and MeOH was evaporated off. The residue was passed
through a short pad of silica gel with hexane-AcOEt (2:1) to
afford crude alcohol. To a solution of the crude alcohol in dry
CH2Cl2 (2.0 mL) was added Dess-Martin periodinane (32.0
mg, 0.76 × 10-1 mmol) at room temperature. After being
stirred for 24 h, the reaction mixture was quenched by addition
of saturated aqueous NaHCO3 and extracted with Et2O. The
extract was washed with aqueous Na2S2O3, water and brine,
dried, and concentrated to dryness. The residue was chro-
matographed with hexane-AcOEt (3:1) to afford 39 (20.0 mg,
1
50%) as a colorless oil: IR 1751, 1693, 1647 cm-1; H NMR δ
(4R *,7R *,8R *,11R *)-6-Ac e t y l-4-(t er t -b u t y ld ip h e n -
ylsiloxy)-7-(p -n it r ob e n zoyloxy)-9-oxa -1-a za t r ic yc lo-
[6.2.1.05,11]u n d ec-5-en -10-on e (38). To a solution of 37 (16.8
mg, 0.23 × 10-1 mmol) in MeOH (2.0 mL) was added 10% HCl
(0.04 mL) at room temperature. After the mixture was stirred
for 24 h, MeOH was evaporated off, and the residue was passed
through a short pad of Na2SO4. To a solution of the crude
alcohol in dry CH2Cl2 (2.0 mL) was added Dess-Martin
periodinane (19.2 mg, 0.45 × 10-1 mmol) at room temperature.
After being stirred for 5 h, the reaction mixture was quenched
by addition of saturated aqueous NaHCO3 and extracted with
Et2O. The extract was washed with aqueous Na2S2O3 and
brine, dried, and concentrated to dryness. The residue was
chromatographed with hexane-AcOEt (4:1) to afford 38 (11.3
mg, 80%) as colorless needles: mp 161-162 °C (hexane-
AcOEt); IR 1761, 1734, 1693 cm-1; 1H NMR δ 8.35 (d, 2H, J )
8.3 Hz), 8.16 (d, 2H, J ) 8.3 Hz), 7.68-7.60 (m, 4H), 7.50-
7.28 (m, 6H), 6.05 (s, 1H), 5.62-5.56 (m, 1H), 5.24 (d, 1H, J )
6.4 Hz), 4.82 (d, 1H, J ) 6.4 Hz), 3.88-3.65 (m, 2H), 2.02-
7.62-7.28 (m, 10H), 5.65 (d, 1H, J ) 5.0 Hz), 5.51-5.43 (m,
1H), 5.06 (dd, 1H, J ) 6.6, 5.0 Hz), 4.83 (d, 1H, J ) 6.6 Hz),
3.86-3.63 (m, 2H), 2.09 (s, 3H), 2.06-1.74 (m, 2H), 1.84 (s,
3H), 1.07 (s, 9H); 13C NMR δ 195.2, 170.2, 157.1, 151.4, 135.5,
135.5, 133.2, 132.4, 130.2, 129.5, 127.9, 127.8, 78.8, 71.9, 63.9,
61.5, 37.8, 36.0 29.3, 27.0, 20.4, 19.3; FABMS m/z 520 (M+
+
1, 8.1);. FABHRMS calcd for C29H34NO6Si 520.2156, found
520.2136.
(4R*,7S*,8R*,11R*)-6-Acetyl-4-(ter t-bu tyldiph en ylsiloxy)-
7-h yd r oxy-9-oxa -1-a za t r icyclo[6.2.1.05,11]u n d ec-5-en -10-
on e (40). To a solution of 39 (1.70 mg, 0.03 × 10-1 mmol) in
MeOH (1.0 mL) was added K2CO3 (0.5 mg, 0.03 × 10-1 mmol)
at room temperature. After the mixture was stirred for 30 min,
MeOH was evaporated off, and the residue was chromato-
graphed with hexane-AcOEt (2:1) to afford 40 (1.50 mg, 96%)
as a colorless oil: IR 3564, 1757 1690 cm-1; 1H NMR δ 7.60-
7.29 (m, 10H), 5.40 (dd, 1H, J ) 4.0, 2.0 Hz), 4.93 (dd, 1H, J
) 11.2, 4.6 Hz), 4.87-4.77 (m, 2H), 3.80-3.64 (m, 2H), 2.59
(d, 1H, J ) 11.2 Hz), 2.01 (s, 3H), 1.96-1.75 (m, 2H), 1.07 (s,
9H); 13C NMR δ 197.4, 157.1, 148.2, 135.5, 134.0, 133.3, 132.5,
130.1, 130.1, 127.9, 127.7, 77.6, 73.6, 63.8, 61.2, 38.2, 36.1, 29.6,
27.0, 19.3; MS m/z 477 (M+, 0.7); HRMS calcd for C27H31NO5-
Si 477.1971, found 477.1973.
1.94 (m, 1H), 1.91 (s, 3H), 1.76-1.64 (m, 1H), 1.14 (s, 9H); 13
C
NMR δ 194.8, 163.4, 156.8, 156.2, 151.0, 135.7, 135.6, 134.3,
132.9, 132.6, 130.9, 130.3, 130.1, 127.9, 127.7, 123.8, 83.0, 76.7,
64.8, 62.5, 37.6, 35.9, 29.8, 26.9, 19.4; FABMS m/z 627 (M+
1, 0.4); FABHRMS calcd for C34H35N2O8Si 627.2163, found
627.2162.
+
(4R *,7S *,8R *,11R *)-6-Ace t yl-4,7-d ih yd r oxy-9-oxa -1-
a za tr icyclo[6.2.1.05,11]u n d ec-5-en -10-on e (41). To a solution
of 40 (60.0 mg, 0.13 mmol) in dry THF (5.0 mL) was added
TBAF (1.0 M solution in THF, 0.15 mL, 0.15 mmol) at room
temperature. After being stirred for 3 h, THF was evaporated
off, and the residue was chromatographed with AcOEt-MeOH
(20:1) to afford the title compound 41 (25.0 mg, 83%) as
colorless needles: mp 166-167 °C (hexane-AcOEt); IR 3599,
(()-8R-Hyd r oxystr ep ta zolon e (2). To a solution of 38 (3.5
mg, 0.56 × 10-2 mmol) in MeOH (1.5 mL) was added K2CO3
(1.00 mg, 0.72 × 10-2 mmol) at room temperature. After being
stirred for 15 min, MeOH was evaporated off, and the residue
was passed through a short pad of silica gel with hexane-
AcOEt (2:1) to afford the crude alcohol. To a solution of the
crude alcohol in dry THF (1.5 mL) was added TBAF (1.0 M
THF solution, 0.02 mL, 0.02 mmol) at room temperature. After
the mixture was stirred for 15 min, THF was evaporated off,
and the residue was chromatographed with AcOEt to afford
the title compound (1.10 mg, 82%) as a colorless oil: IR 3593,
1
3560, 3389, 1757, 1692 cm-1; H NMR δ 5.41 (brs, 1H), 5.28
(dd, 1H, J ) 11.2, 5.0 Hz), 4.96 (dd, 1H, J ) 6.6, 5.0 Hz), 4.83
(d, 1H, J ) 6.6 Hz), 3.84-3.48 (m, 2H), 2.77 (d, 1H, J ) 11.2
Hz), 2.41 (s, 3H), 2.02-1.80 (m, 2H), 1.90 (brs, 1H); 1H NMR-
(Acetone-d6) δ 5.36 (dd, 1H, J ) 10.6, 5.0 Hz), 5.26 (dd, 1H, J
) 5.9, 3.0 Hz), 4.90 (dd, 1H, J ) 6.3, 5.0 Hz), 4.80 (d, 1H, J )
6.3 Hz), 4.55 (d, 1H, J ) 10.6 Hz), 4.43 (d, 1H, J ) 3.0 Hz),
3.59-3.44 (m, 2H), 2.32 (s, 3H), 1.92-1.60 (m 2H); 13C
NMR(CD3OD) δ 200.2, 160.2, 149.7, 136.4, 78.7, 76.7, 62.6,
62.5, 38.7, 35.9, 29.8; FABMS m/z 240 (M+ + 1, 25); FABHRMS
calcd for C11H14NO5 240.0872, found 240.0875.
3391, 1753, 1688 cm-1 1H NMR δ 5.38 (t, 1H, J ) 3.3 Hz),
;
5.07-4.98 (m, 2H), 4.70 (d, 1H, J ) 6.3 Hz), 3.77-3.46 (m,
1
2H), 2.41 (s, 3H), 2.02-1.89 (m, 1H), 1.83-1.67 (m, 1H); H
NMR (CD3OD) δ 5.41 (dd, 1H, J ) 3.3, 2.6 Hz), 5.06 (dd, 1H,
J ) 6.3, 0.7 Hz), 4.94 (d, 1H, J ) 0.7 Hz), 4.65 (d, 1H, J ) 6.3
Hz), 3.69-3.45 (m, 2H), 2.39 (s, 3H), 1.97-1.84 (m, 1H), 1.73-
1.54 (m, 1H); 13C NMR δ 198.5, 156.8, 153.2, 133.6, 81.2, 79.3,
J . Org. Chem, Vol. 69, No. 6, 2004 1811

Nomura and Mukai
(4R*,7S*,8R*,11R*,1′R*)- a n d (4R*,7S*,8R*,11R*,1′S*)-
4-(t er t -B u t y ld ip h e n y ls ilo x y )-7-h y d r o x y -6-[1′-(m e t h -
oxym eth oxy)eth yl]-9-oxa -1-a za tr icyclo[6.2.1.05,11]u n d ec-
5-en -10-on e (42). To a solution of 35 (34.9 mg, 0.73 × 10-1
mmol) in dry CH2Cl2 (2.0 mL) were added MOMCl (0.02 mL,
0.26 mmol) and iPr2NEt (0.04 mL, 0.24 mmol) at room
temperature. The reaction mixture was refluxed for 8 h, and
CH2Cl2 was evaporated off. The residue was passed through
a short pad of silica gel with hexane-AcOEt (2:1) to afford
the crude MOM ether derivatives. To a solution of the crude
products and CeCl3 (23.4 mg, 0.095 mmol) in MeOH (2.0 mL)
was added NaBH4 (3.00 mg, 0.08 mmol) at 0 °C. The reaction
mixture was stirred for 10 min at 0 °C, and MeOH was
evaporated off. The residue was diluted with water and
extracted with AcOEt. The extract was washed with water,
dried, and concentrated to dryness. The residue was chro-
matographed with hexane-AcOEt (2:1) to afford 42 (34.4 mg,
90%) as colorless needles: mp 147-148 °C (hexane-AcOEt);
IR 3564, 3479, 1751 cm-1; 1H NMR δ 7.69-7.52 (m, 4H), 7.50-
7.32 (m, 6H), 5.15 (dd, 1H × 50/100, J ) 3.4, 2.0 Hz), 4.97 (d,
1H × 50/100, J ) 4.9 Hz), 4.90-4.75 (m, 5H × 50/100), 4.67
(d, 1H × 50/100, J ) 6.3 Hz), 4.41 (d, 1H × 50/100, J ) 6.8
Hz), 4.37 (d, 1H × 50/100, J ) 6.8 Hz), 4.25-4.33 (m, 3H ×
50/100), 3.92 (q, 1H × 50/100, J ) 6.3 Hz), 3.77-3.62 (m, 2H),
3.17 (s, 3H × 50/100), 3.15 (s, 3H × 50/100), 1.82-1.54 (m,
2H), 1.11 (d, 3H × 50/100, J ) 6.3 Hz), 1.08 (s, 9H × 50/100),
1.07 (s, 9H × 50/100), 1.04 (d, 3H × 50/100, J ) 6.8 Hz); 13C
NMR δ 158.1, 157.8, 138.1, 137.9, 135.7, 135.6, 135.6, 135.5,
135.1, 134.6, 133.2, 133.1, 133.0, 130.1, 130.0, 129.9, 127.9,
127.8, 127.7, 127.6, 95.0, 94.2, 78.4, 78.1, 74.7, 74.0, 69.7, 67.1,
64.2, 63.8, 61.1, 60.9, 55.4, 55.1, 38.2, 38.1, 35.3, 35.0, 26.9,
26.9, 20.3, 19.3, 19.3, 18.1; FABMS m/z 524 (M+ + 1, 3.0);
FABHRMS calcd for C29H38NO6Si 524.2468, found 524.2450.
Anal. Calcd for C29H37NO6Si: C, 66.51; H, 7.12; N, 2.67.
Found: C, 66.40; H, 7.08; N, 2.61.
Com p ou n d 38 fr om 42. To a solution of 42 (34.1 mg, 0.65
× 10-1 mmol) in dry benzene (0.03 mL) were added PPh3 (51.2
mg, 0.20 mmol) and p-nitrobenzoic acid (32.7 mg, 0.20 mmol)
at room temperature. DEAD (0.04 mL, 0.26 mmol) was then
added to the reaction mixture, which was heated at 70 °C for
3 h. The reaction mixture was passed through a short pad of
silica gel with hexane-AcOEt (4:1) to afford the crude p-
nitrobenzoate. To a solution of the crude p-nitrobenzoate in
dry THF (1.5 mL) was added concentrated HCl solution (0.40
mL) at room temperature. After being stirred for 3 h at 60 °C,
the reaction mixture was neutralized with saturated aqueous
NaHCO3 and extracted with AcOEt. The extract was washed
with water and brine, dried, and concentrated to dryness. To
a solution of the crude alcohol in dry CH2Cl2 (1.5 mL) was
added Dess-Martin periodinane (138 mg, 0.33 mmol) at room
temperature. After being stirred for 12 h, the reaction mixture
was quenched by addition of saturated aqueous NaHCO3 and
extracted with Et2O. The extract was washed with aqueous
Na2S2O3, water, and brine, dried, and concentrated to dryness.
The residue was chromatographed with hexane-AcOEt (5:1)
to afford 38 (26.3 mg, 65%).
Ack n ow led gm en t. We thank Drs. Y.-Q. Tang, D.
Wunderlich, I. Sattler, and S. Grabley of the Hans-Kno¨ll
Institute of Natural Products Research, Germany, for
1
generously providing H and 13C NMR spectra of the
natural 8R-hydroxystreptazolone.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 2, 11, 21, 25a ,b, 26a , 32, 34, 38, 39,
40, and 41; preparation and characterization data for com-
pounds 25a -d , 26a -d , 27-32. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0356816
1812 J . Org. Chem., Vol. 69, No. 6, 2004