First asymmetric total synthesis of synerazol, an antifungal antibiotic, and determination of its absolute stereochemistry

Article abstract of DOI:10.1021/jo050664x

By synthesizing two possible diastereomers, the first asymmetric total synthesis of synerazol, an antifungal antibiotic, has been accomplished, allowing determination of its absolute stereochemistry. A more practical second generation route was also estab

Full text of DOI:10.1021/jo050664x

First Asymmetric Total Synthesis of Synerazol, an Antifungal
Antibiotic, and Determination of Its Absolute Stereochemistry
Yujiro Hayashi,*,† Mitsuru Shoji,† Takasuke Mukaiyama,† Hiroaki Gotoh,†
Shinpei Yamaguchi,† Munetaka Nakata,‡ Hideaki Kakeya,§ and Hiroyuki Osada§
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Graduate School of BASE (Bio-Applications and Systems Engineering),
Tokyo University of Agriculture and Technology, Naka-cho, Koganei, Tokyo 184-8588, and Antibiotics
Laboratory, Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
hayashi@ci.kagu.tus.ac.jp
Received April 5, 2005
By synthesizing two possible diastereomers, the first asymmetric total synthesis of synerazol, an
antifungal antibiotic, has been accomplished, allowing determination of its absolute stereochemistry.
A more practical second generation route was also established. The key steps are racemization-
free deprotection of a TIPS group and introduction of a methyl ether by DMD oxidation of the
benzylidene moiety in a substrate having a small protecting group.
Introduction
Its structure, including the absolute stereochemistry, has
been unambiguously determined by a single-crystal X-ray
analysis of its 12,13-dibromo derivative.2b Azaspirene,
possessing the same core structure, has been isolated
from the fungus Neosartorya sp. by Kakeya and Osada
et al. in 20023 and found to inhibit endothelial migration
induced by vascular endothelial growth factor. Because
of the unprecedented, densely functionalized core struc-
ture of the pseurotins and azaspirene, their total syn-
thesis poses a significant challenge.4 We have completed
the first total synthesis of a member of this class of com-
pounds, that of azaspirene, in 2002.5 Through this asym-
metric total synthesis the absolute stereochemistry of
azaspirene was determined. Our group also accomplished
the asymmetric total syntheses of pseurotin A and of 8-O-
demethylpseurotin A in 2003.6 Recently Tadano’s group
reported the total syntheses of pseurotin A, 8-O-demeth-
ylpseurotin A, and azaspirene from D-glucose.7 Despite
Synerazol is an antifungal antibiotic isolated by Ando
and co-workers in 1991 from the cultured broth of
Aspergillus fumigatus SANK 10588.1 Synerazol is active
against Candida albicans and other fungi and shows
marked synergistic activity with azole-type antifungal
agents. Synerazol contains a highly oxygenated 1-oxa-7-
azaspiro[4.4]non-2-ene-4,6-dione skeleton with benzoyl
and epoxyalkene substituents. The core structure, a
hetero-spirocyclic γ-lactam, is also found in the pseurotins2
and azaspirene.3 Pseurotin A, isolated from a culture
broth of Pseudeurotium ovalis (strain S2269/F) in 1976
by Bloch et al.,2a was reported to inhibit chitin synthase
by Sterner et al. in 19932c and also found to induce cell
differentiation of PC12 cells by Komagata et al. in 1996.2d
* To whom correspondence should be addressed. Phone: (+81)3-
5228-8318. Fax: (+81)3-5261-4631.
† Tokyo University of Science.
‡ Tokyo University of Agriculture and Technology.
§ Discovery Research Institute, RIKEN.
(4) For synthetic studies on the pseurotins, see: (a) Dolder, M.; Shao,
X.; Tamm, C. Helv. Chim. Acta 1990, 73, 63. (b) Shao, X.; Dolder, M.;
Tamm, C. Helv. Chim. Acta 1990, 73, 483. (c) Su, Z.; Tamm, C. Helv.
Chim. Acta 1995, 78, 1278. (d) Su, Z.; Tamm, C. Tetrahedron 1995,
51, 11177. (e) Aoki, S.; Ohi, T.; Shimizu, K.; Shiraki, R.; Takao, K.;
Tadano, K. Heterocycles 2002, 58, 57.
(5) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.;
Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am.
Chem. Soc. 2002, 124, 12078.
(6) Hayashi, Y.; Shoji, M.; Yamaguchi, S.; Mukaiyama, T.; Yamagu-
chi, J.; Kakeya, H.; Osada, H. Org. Lett. 2003, 5, 2287.
(1) Ando, O.; Satake, H.; Nakajina, M.; Sato, A.; Nakamura, T.;
Kinoshita, T.; Furuya, K.; Haneishi, T. J. Antibiot. 1991, 44, 382.
(2) (a) Bloch, P.; Tamm, C.; Bollinger, P.; Petcher, T. J.; Weber, H.
P. Helv. Chim. Acta 1976, 59, 133. (b) Weber, H. P.; Petcher, T. J.;
Bloch, P.; Tamm, C. Helv. Chim. Acta 1976, 59, 137. (c) Wenke, J.;
Anke, H.; Sterner, O. Biosci. Biotechnol. Biochem. 1993, 57, 961. (d)
Komagata, D.; Fujita, S.; Yamashita, N.; Saito, S.; Morino, T. J.
Antibiot. 1996, 49, 958.
(3) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.;
Osada, H. Org. Lett. 2002, 4, 2845.
10.1021/jo050664x CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/08/2005
J. Org. Chem. 2005, 70, 5643-5654
5643

Hayashi et al.
FIGURE 1. The structures of synerazol (1), pseurotin A (2), and azaspirene (3).
SCHEME 1. First Generation Retrosynthetic
the similarity of their structures, the reported biological
properties of synerazol, pseurotin A, and azaspirene are
rather different as described above. Systematic compari-
son of the biological properties of these natural products
and their derivatives is highly desirable, and a sufficient
quantity of not only the natural products but also several
derivatives is required for such biological study. As we
had established a synthetic method for pseurotin A and
azaspirene, we began to investigate the total synthesis
of synerazol, the last member of this family of natural
products remaining unsynthesized.The absolute stereo-
chemistry of synerazol was unknown when we started
this synthesis. We have determined this unambiguously
by the first asymmetric total synthesis of synerazol as
described in the first part of this paper8 and in the second
part a more practical synthesis of the natural isomer
involving highly diastereoselective reactions. Recently
Igarashi and co-workers have also determined the abso-
lute stereochemistry using the modified Mosher’s MTPA
method on an alcohol derived from synerazol.9
Analysis
) >98:2). Deprotection and oxidation afforded side-chain
aldehyde (-)-6, which was used immediately in the next
reaction because it gradually decomposed. Starting from
L-tartaric acid diethyl ester (+)-8, the enantiomer (+)-6
was also prepared by the same route.
With side-chain epoxyaldehydes (-)-6 and (+)-6 in
hand, their reaction with ketone 7, prepared by our
established method,5,6 was examined.
The lithium enolate of 7 reacted with side-chain epoxy
aldehyde (-)-6, affording the aldol product 17 in 45%
yield (diastereomer ratio ) 2:1) with recovery of ketone
7 in 49% yield (Scheme 3). Thus, the yield based on the
recovered starting material (BRSM) was 88%. Oxidation
of aldol 17 with the Dess-Martin periodinane (DMP)11
in CH2Cl2 proceeded smoothly, providing the 1,3-dike-
tone, which owing to the mild acidity of silica gel was
transformed into azaspiro compound 18 via cyclization
and dehydration reactions during purification with thin-
layer chromatography (TLC).
Results and Discussion
First Generation Synthesis of Synerazol. Ret-
rosynthetic Analysis. While the absolute stereochem-
istry of synerazol was unknown, we postulated that the
absolute stereochemistry of the 1-oxa-7-azaspiro[4.4]non-
2-ene-4,6-dione ring system would likely be the same as
pseurotin A2b and azaspirene.5 As there was no informa-
tion on the side-chain epoxyalkene, we decided to syn-
thesize both possible diastereomers, 4 and 5.
When 18 was treated with dimethyldioxirane (DMD)12
at low temperature, selective oxidation of the benzylidene
was achieved, affording diol 19 in 40% yield with 33%
recovery of 18. As overoxidation proceeded on prolonged
reaction time or at higher temperature, quenching the
reaction at an early stage and repeating the oxidation
on recovered 18 are recommended. A subsequent DMP
oxidation afforded benzoyl derivative 20 in good yield
(95%).
Using the methodology developed for the synthesis of
pseurotin A and azaspirene, we planned to prepare the
diastereoisomers 4 and 5 from ketone 7 containing the
lactam moiety and epoxyaldehydes (-)-6 and (+)-6,
respectively, by aldol condensation followed by functional
group transformations (Scheme 1).
Synthesis of the Epoxyaldehyde. The enantiomeri-
cally pure side-chain aldehyde has been prepared in a
highly stereoselective manner (Scheme 2). The synthesis
started from D-tartaric acid diethyl ester (-)-8, which was
converted to epoxy diester (+)-10 by Saito’s procedure.10
Careful optimization of the reaction conditions enabled
the selective monoreduction of this diester to hydroxy
ester (+)-11 in reasonable yield (71%). Protection of the
alcohol with TBSCl and imidazole, followed by reduction
and oxidation, afforded aldehyde (+)-14. Wittig reaction
provided the Z-olefin with excellent stereoselectivity (Z:E
In our previous total synthesis of pseurotin A,6 suc-
cessful transformation of a hydroxy group into the
corresponding methyl ether was accomplished by treat-
ment of 23 with AcCl in MeOH to afford pseurotin A in
25% yield (eq 1, Scheme 4). When N,O-acetal 25, pre-
pared by removal of the TIPS group of 20, was treated
with AcCl in MeOH in order to convert the hydroxy group
into a methoxy group and form 4, decomposition occurred
because of the acid instability of the epoxyalkene moiety
(eq 2, Scheme 4). Even in the presence of a milder acid
(7) (a) Aoki, S.; Ohi, T.; Shimizu, K.; Shiraki, R.; Takao, K.; Tadano,
K. Heterocycles 2004, 62, 161. (b) Aoki, S.; Ohi, T.; Shimizu, K.; Shiraki,
R.; Takao, K.; Tadano, K. Bull. Chem. Soc. Jpn. 2004, 77, 1703.
(8) We have orally presented the first synthesis of synerazol and
determination of its absolute stereochemistry at the following meet-
ing: Hayashi, Y.; Shoji, M.; Mukaiyama, T.; Yamaguchi, S.; Gotoh,
H.; Kakeya, H.; Osada, H. Abstracts of Papers, 84 Annual Meeting of
Japan Chemical Society, Kobe, Japan, March 27, 2004; p 981.
(9) Igarashi, Y.; Yabuta, Y.; Furumai, T. J. Antibiot. 2004, 57, 537.
(10) Saito, S.; Komada, K.; Morowake, T. Org. Synth. 1995, 73, 184.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (d) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(12) (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377. (b) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka,
T. Tetrahedron 2000, 56, 8855.
5644 J. Org. Chem., Vol. 70, No. 14, 2005

Asymmetric Total Synthesis of Synerazol
SCHEME 2. Synthetic Scheme of Epoxyaldehyde (-)-6 and (+)-6
SCHEME 3. Synthesis of 4
SCHEME 4
such as TsOH‚H2O or pyridinium p-toluenesulfonate
(PPTS), decomposition also occurred without formation
of 4.
We next employed the Williamson ether synthesis.
When 20 was treated with triisopropylsilyl trifluo-
romethanesulfonate (TIPSOTf) and 2,6-lutidine, O-sily-
J. Org. Chem, Vol. 70, No. 14, 2005 5645

Hayashi et al.
SCHEME 5. Synthesis of 5
SCHEME 6
lated 21 was formed quantitatively, the structure of
which was assigned by IR analysis. The yield of the
methyl ether 22 was poor (10%) when 21 was treated
with Ag2O and MeI.13 Despite extensive experimentation
on this methyl ether formation under several different
reaction conditions using reagents such as MeI and NaH,
decomposition occurred because of the instability of the
epoxyalkene moiety and the yield did not exceed 10%.
Even though the yield of 22 was not satisfactory, the first
total synthesis of 4 was accomplished by deprotection of
the TIPS group with NH4F. Though the reaction was slow
even in the presence of an excess amount of NH4F (34
equiv), 4 was isolated in 55% yield with 30% recovery of
22 after 11 h at room temperature.
Though we had accomplished the first total synthesis
of synerazol and thus determined its absolute stereo-
chemistry, this synthetic route is not practical for large
scale preparation and derivatization, because of the poor
yield for formation of the methyl ether 22. A more
efficient route is therefore required.
Second Generation Synthesis. An interesting phe-
nomenon was observed when oxidation of the benzylidene
moiety in model 32 was examined. When 32 was treated
with DMD in MeOH, methyl ether 33 was obtained in
93% yield (eq 3, Scheme 6). In this reaction the inter-
mediate epoxide 34 was formed, which was trapped with
MeOH to afford methyl ether 33.
Should it be possible to oxidize the benzylidene moiety
of azaspiro compound 35 with DMD to afford methyl
ether 36 directly (eq 4, Scheme 6), the poor reaction for
introducing the methyl ether in the first generation
synthesis could be avoided.
Though oxidation of 18 with DMD was investigated
under anhydrous conditions several times, only diol 19
was obtained without formation of the desired methyl
ether (Scheme 3). The failure of the introduction of
methyl ether would be explained as follows by the
comparison between 18 and 32. Because it would be more
crowded around the benzylidene moiety in the case of 18,
MeOH could not react with the intermediate epoxide, but
water, which is much smaller than MeOH and contami-
nated in the solvent, reacted with the epoxide, affording
diol 19. If this TIPS group can be substituted with a much
smaller protecting group, such as triethylsilyl (TES) or
By the same synthetic procedure, starting from the
enantiomeric aldehyde (+)-6, the diastereomer 5 was also
synthesized as shown in Scheme 5.
The 1H NMR and 13C NMR spectra of 4, 5, and natural
synerazol were very similar. Chiral HPLC analysis14
showed that the retention time of natural synerazol is
identical to that of the isomer 4 derived from D-tartaric
acid diethyl ester. The optical rotation of synthetic 4
([R]22 +22.6 (c 0.14, CHCl3)) is in good agreement with
D
that of literature data1 for the natural product ([R]25
D
+22.9 (c 0.55, CHCl3)). These results clearly indicate that
4 is the natural isomer of synerazol.
(13) Greene, A. E.; Drian, C. L.; Crabbe, P. J. Am. Chem. Soc. 1980,
102, 7583.
(14) HPLC analysis conditions: CHIRACEL AD-H column, 2-PrOH/
hexane ) 1/3, 1.0 mL/min; retention times, 12.82 min (4 + natural
synerazol), 13.00 min, 13.65 min (5 + natural synerazol).
5646 J. Org. Chem., Vol. 70, No. 14, 2005

Asymmetric Total Synthesis of Synerazol
SCHEME 7
SCHEME 8
SCHEME 9
SCHEME 10
trimethylsilyl (TMS), introduction of the methyl ether
might be possible. Exchanging the protecting group at
the stage of 18 would be inadequate because of isomer-
ization, which we observed in our previous total synthesis
of azaspirene.5 That is, when 37 was treated with NH4F
in MeOH at room temperature, complete racemization
proceeded (eq 5, Scheme 7). As there is a â-ketoamide
moiety in 38, racemization can occur by the retro-aldol
reaction via stable conjugated anion 39. In fact isomer-
ization occurred when 18 was treated with NH4F.
Though a similar racemization might well be expected
with the substrate 7, which also has a â-ketoamide
moiety, the racemization of 7 was in fact found to be slow
(vide infra). That is, when 7 (>99% ee) was treated with
tetrabutylammonium fluoride (TBAF) in THF at room
temperature and the resulting alcohol 40 was then
protected with TESOTf and 2,6-lutidine, mono TES ether
41 was obtained quantitatively in 84% ee. When the
deprotection was carried out at lower temperature (-30
°C), the racemization was completely suppressed, and the
TES ether 41 was obtained in excellent optical purity
(>99% ee) (eq 6, Scheme 8). The corresponding TMS
ether 42 was also prepared without racemization (>99%
ee) (eq 7, Scheme 8).
TABLE 1. DMD Oxidation of Benzylidene Derivatives
18, 45, 46
yield (%)a
entry
R
time (h)
A
B
1
2
3
TIPS (18)
TES (45)
TMS (46)
12
4
4
0
46
30
10
30
65 (47)
a Isolated yield.
By following the established two-step procedure, ben-
zylidene derivatives 45 and 46 containing TES and TMS
groups have been synthesized from 41 and 42 as shown
in eq 8 (Scheme 9).
With the benzylidene derivatives 45 and 46 in hand,
the oxidation with DMD was investigated. The ben-
zylidene derivatives with different protecting groups were
treated with DMD in MeOH in the presence of MS3A at
low temperature (-60 °C), with the results summarized
in Table 1.
The bulkiness of the silyl protecting group clearly
affected the ratio of methyl ether A to diol B greatly (eq
9, Scheme 10). In the case of TIPS ether 18, the reaction
was slow, affording diol in 46% yield with 38% recovery
J. Org. Chem, Vol. 70, No. 14, 2005 5647

Hayashi et al.
SCHEME 11
SCHEME 12
TABLE 2. Racemization during Deprotection of TIPS
Group
of the starting material 18. None of the desired methyl
ether was formed. The methyl ether and diol were formed
in the same yield (30%) in the case of TES ether 45.
Unlike these unsuccessful results, methyl ether 47 was
obtained in an acceptable yield (65%) when TMS ether
46 was oxidized.
As the desired methyl ether 47 had been obtained, the
total synthesis was completed by carrying out the re-
maining two steps, oxidation with DMP and deprotection
of the silyl group with NH4F, affording synerazol (1) in
good yield (eq 10, Scheme 11).
Racemization Mechanism. Though a practical total
synthesis of synerazol has been accomplished, the dif-
ferent racemization behavior of substrates 37 and 7
during the deprotection of the TIPS group appears
strange: whereas the azaspiro compound 37 completely
racemizes, no racemization of γ-lactam 7 occurs at all (eqs
5 and 6). In our previous total synthesis of azaspirene,
we found that hydroxy azaspiro compound 49 does not
racemize and affords azaspirene in the last step of the
total synthesis.5 In this case, a hydrogen-bonding inter-
action as shown in 50 may prevent racemization (eq 11,
Scheme 12).
As the hydroxy group of γ-lactam 7 might play a role,
we examined the racemization of 3-methoxy γ-lactam 51.
We also investigated dimethoxy compound 52. Their
racemization behavior is summarized in Table 2. No
racemization occurred in the cases of γ-lactam 7 and
methoxy γ-lactam 51, whereas dimethoxy derivative 52
completely racemized. Hence the 3-hydroxy does not
affect the racemization. In the case of 52, however, the
anion generated by a retro-aldol reaction is very stable
as a result of the delocalization shown in 53, and this
would be the driving force for the facile racemization.
entry
SMa
time (h)
yield (%)b
eec (%)
1
2
3
7
51
52
72
20
20
92
50
96
>99
>99
0
a Starting material. b Isolated yield. c Enantiomeric excess of
alcohol.
The compounds 22, 31, and 48 did not isomerize at all,
when the silyl protecting group was removed. This would
be because of a hydrogen-bonding interaction as shown
in 54, which would be formed by trapping the intermedi-
ate alkoxide with solvent MeOH. As for the racemization,
FIGURE 2. Hydrogen-bonding interaction in 54.
which proceeded via retro-aldol reaction, the following
has been determined: (1) When there is a hydrogen-
bonding interaction, racemization dose not proceed as
shown in 22, 31, 48, and 49. (2) When there is no
hydrogen-bonding interaction and the generated anion
is very stable owing to the delocalization such as in 39
and 53, racemization is a facile process as shown in 18,
37, and 52; otherwise it is a slow process as shown in 7
and 51.
Conclusion
In summary, we have succeeded in the total syntheses
of synerazol, an antifungal antibiotic, by two routes in a
5648 J. Org. Chem., Vol. 70, No. 14, 2005

Asymmetric Total Synthesis of Synerazol
(FAB) [M - C4H9]+ calcd for C6H13O3Si 161.0634, found
highly stereoselective manner for the first time. In the
first generation synthesis, two possible isomers were
synthesized, and the absolute stereochemistry was de-
termined. In the second generation synthesis, which is
more practical than the first, the key steps are racem-
ization-free deprotection of a TIPS group and introduction
of a methyl ether by DMD oxidation of the benzylidene
moiety in a substrate having a small protecting group.
The present synthesis of synerazol combined with our
previous total syntheses of the pseurotins and azaspirene
makes possible their derivatization and large-scale prepa-
ration, which will pave the way for biological study of
this class of natural products.
161.0630; [R]21 +21.6 (c 1.41, CHCl3).
D
(2S,3R)-2,3-Epoxy-4-(tert-butyldimethylsiloxy)-buta-
nal ((+)-14). To a CH2Cl2 (95 mL) and DMSO (95 mL) solution
of (+)-13 (20.5 g, 93.9 mmol) and NEt3 (40 mL, 282 mmol) was
added SO3‚Py (26.9 g, 169 mmol) at 0 °C. After stirring the
reaction mixture for 1 h at that temperature, the reaction was
quenched by the addition of pH 7.0 phosphate buffer, the
organic materials were extracted with diethyl ether four times,
and the combined organic extracts were washed with brine
three times, dried over anhydrous MgSO4, and concentrated
in vacuo after filtration. The crude aldehyde (+)-14 (23.3 g)
was directly used in the next experiment: 1H NMR (400 MHz,
CDCl3) δ 0.04 (3H, s), 0.05 (3H, s), 0.86 (9H, s), 3.32 (1H, dd,
J ) 6.3, 1.7 Hz), 3.33-3.37(1H, m), 3.75 (1H, dd, J ) 12.3, 3.8
Hz), 3.95 (1H, dd, J ) 12.3, 2.4 Hz), 9.04 (1H, d, J ) 6.3 Hz);
13C NMR (100 MHz, CDCl3) δ -5.4, 25.8, 31.6, 56.2, 56.7,
61.3, 198.0; FT-IR (neat) ν 2956, 2929, 2858, 1731, 1473, 1254,
1132, 1107, 839, 779 cm-1; HRMS (FAB) [M + H]+ calcd for
C10H21O3Si 217.1260, found 217.1226.
Experimental Section
(2S,3R)-2,3-Epoxy-4-hydroxybutanoic Acid Ethyl Ester
((+)-11). To a EtOH (380 mL) solution of (+)-10 (20.6 g, 106
mmol) was added NaBH4 (3.23 g, 85.1 mmol) at 0 °C. After
stirring the reaction mixture for 2 h at that temperature, the
reaction was quenched by the addition of pH 7.0 phosphate
buffer, and the organic materials were extracted with chloro-
form three times, dried over anhydrous Na2SO4, and concen-
trated in vacuo after filtration. Purification by silica gel column
chromatography (ethyl acetate/hexane ) 1:4-1:2) gave 11.0 g
(71%) of alcohol (+)-11 as a colorless solid: 1H NMR (400 MHz,
CDCl3) δ 1.29 (3H, t, J ) 7.1 Hz), 1.79 (1H, bs), 3.33-3.39
(1H, m), 3.51 (1H, d, J ) 2.0 Hz), 3.74 (1H, dd, J ) 13.1, 3.3
Hz), 3.98 (1H, dd, J ) 13.1 2.1 Hz), 4.14-4.29 (2H, m); 13C
NMR (100 MHz, CDCl3) δ 14.0, 50.1, 57.8, 60.0, 61.7, 168.8;
FT-IR (neat) ν 3392, 2987, 1743, 1736, 1331, 1247, 1207, 1031,
781, 627 cm-1; HRMS (FAB) [M + H]+ calcd for C6H11O4
(2R,3R)-(Z)-2,3-Epoxy-4-(tert-butyldimethylsiloxy)-hept-
4-ene ((+)-15). To a THF (235 mL) solution of [n-PrPPh3]+-
Br- (42.0 g, 109 mmol) was added a hexane solution of n-BuLi
(2.44 M, 40 mL, 98.6 mmol) at 0 °C, and the reaction mixture
was stirred for 30 min. To the reaction mixture was added a
THF solution (40 mL) of crude aldehyde (+)-14 (23.3 g) at 0
°C, and the reaction mixture was stirred for 30 min. The
reaction was quenched by the addition of pH 7.0 phosphate
buffer, the organic materials were extracted with diethyl ether
four times, and the combined organic extracts were washed
with brine three times, dried over anhydrous MgSO4, and
concentrated in vacuo after filtration. Purification by silica gel
column chromatography (diethyl ether/pentane ) 1:4) gave
18.9 g (82%, Z/E ) >98/2, two steps) of olefin (+)-15 as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.06 (3H, s),
0.07 (3H, s), 0.89 (9H, s), 1.02 (3H, t, J ) 7.5 Hz), 2.05-2.25
(2H, m), 2.95-3.00 (1H, m), 3.51 (1H, dd, J ) 9.0, 1.9
Hz), 3.72 (1H, dd, J ) 11.9, 4.5 Hz), 3.83 (1H, dd, J ) 11.9,
3.3 Hz), 5.03 (1H, ddt, Jd ) 11.0, 9.1 Hz, Jt ) 1.4 Hz), 5.70
(1H, dt, Jd ) 11.0 Hz, Jt ) 7.5 Hz); 13C NMR (100 MHz, CDCl3)
δ -5.3, -5.3, 14.2, 18.3, 21.1, 25.9, 51.8, 60.0, 63.2, 125.8,
138.5; FT-IR (neat) ν 2958, 2929, 2858, 1473, 1464, 1255,
1140, 1107, 837, 777 cm-1; HRMS (FAB) [M + H]+ calcd for
147.0657, found 147.0668; [R]18 +33.6 (c 1.33, CHCl3); mp
D
43.0-44.0 °C.
(2S,3R)-2,3-Epoxy-4-(tert-butyldimethylsiloxy)-buta-
noic Acid Ethyl Ester ((+)-12). To a DMF (295 mL) solution
of (+)-11 (17.8 g, 122 mmol) and imidazole (16.9 g, 248 mmol)
was added TBSCl (27.6 g, 183 mmol) at 0 °C. After stirring
the reaction mixture for 1.5 h at that temperature, the reaction
was quenched by the addition of pH 7.0 phosphate buffer, the
organic materials were extracted with ethyl acetate three
times, and the combined organic extracts were washed with
brine three times, dried over anhydrous Na2SO4, and concen-
trated in vacuo after filtration. The crude (+)-12 (40.8 g) was
directly used in the next reaction: 1H NMR (400 MHz, CDCl3)
δ 0.03 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 1.28 (3H, t, J ) 7.1
Hz), 3.27-3.31 (1H, m), 3.40 (1H, d, J ) 1.9 Hz), 3.76 (1H, dd,
J ) 12.3, 3.6 Hz), 3.89 (1H, dd, J ) 12.3, 2.6 Hz), 4.15-4.26
(2H, m); 13C NMR (100 MHz, CDCl3) δ -5.4, -5.4, 14.1, 18.3,
25.8, 50.3, 58.2, 61.4, 61.6, 169.1; FT-IR (neat) ν 2956, 2931,
2857, 1755, 1739, 1473, 1198, 838, 779 cm-1; HRMS (FAB)
C13H27O2Si 243.1780, found 243.1792; [R]23 +9.4 (c 1.17,
D
CHCl3).
(2R,3R)-(Z)-2,3-Epoxyhept-4-en-1-ol (+)-16. To a THF (90
mL) solution of (+)-15 (16.4 g, 67.7 mmol) was added a THF
solution of TBAF (1.0 M, 88 mL, 88 mmol) at 0 °C. After
stirring the reaction mixture for 15 min at that temperature,
the reaction was quenched by the addition of pH 7.0 phosphate
buffer, and the organic materials were extracted with diethyl
ether four times, dried over anhydrous MgSO4, and concen-
trated in vacuo after filtration. Purification by silica gel column
chromatography (diethyl ether/pentane ) 1:10-1:1) gave 8.22
g (95%) of alcohol (+)-16 as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 1.02 (3H, t, J ) 7.5 Hz), 2.10-2.32 (2H, m), 3.05 (1H,
t, J ) 2.4 Hz), 3.61-3.73 (2H, m), 3.95 (1H, ddd, J ) 12.6,
5.1, 2.4 Hz), 5.04 (1H, ddt, Jd ) 10.9, 9.1 Hz, Jt ) 1.5 Hz),
5.73 (1H, dt, Jd ) 11.0 Hz, Jt ) 7.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 14.1, 21.0, 51.4, 59.9, 61.2, 125.2, 139.0; FT-IR (neat)
ν 3410, 2962, 2925, 2854, 1458, 1074, 874, 727 cm-1; HRMS
(FAB) calcd for C7H12O2 128.0837, found 128.0836; [R]21D +78.1
(c 1.44, CHCl3).
(2S,3R)-(Z)-2,3-Epoxyhept-4-enal ((-)-6). To a CH2Cl2 (4
mL) and DMSO (4 mL) solution of alcohol (+)-16 (500 mg, 3.90
mmol) and NEt3 (1.65 mL, 11.7 mmol) was added SO3‚Py (1.18
mg, 7.41 mmol) at 0 °C. After stirring the reaction mixture
for 1 h at that temperature, the reaction was quenched by the
addition of pH 7.0 phosphate buffer, the organic materials were
extracted with diethyl ether four times, and the combined
organic extracts were washed with brine three times, dried
over anhydrous MgSO4, and concentrated in vacuo after
[M + H]+ calcd for C12H25O4Si 261.1522, found 261.1522; [R]16
+18.8 (c 1.09, CHCl3).
D
(2R,3R)-2,3-Epoxy-4-(tert-butyldimethylsiloxy)butan-
1-ol ((+)-13). To a MeOH (440 mL) solution of crude (+)-12
(40.8 g) was added NaBH4 (13.9 g, 367 mmol) at 0 °C. After
30 min, the reaction mixture was warmed to room temperature
and stirred for 1.5 h at that temperature. The reaction was
quenched by the addition of pH 7.0 phosphate buffer, and the
organic materials were extracted with chloroform three times,
dried over anhydrous MgSO4, and concentrated in vacuo after
filtration. Purification by silica gel column chromatography
(ethyl acetate/hexane ) 1:9-1:1) gave 25.3 g (95%, two steps)
of alcohol (+)-13 as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 0.02 (3H, s), 0.03 (3H, s), 0.85 (9H, s), 2.30 (1H, bs), 3.02-
3.10 (2H, m), 3.59 (1H, dd, J ) 12.7, 4.2 Hz), 3.66 (1H, dd, J
) 12.0, 4.3 Hz), 3.83 (1H, dd, J ) 12.0, 2.7 Hz), 3.88 (1H, dd,
J ) 12.7, 1.9 Hz); 13C NMR (100 MHz, CDCl3) δ -3.6, -5.3,
25.7, 25.9, 55.7, 55.9, 61.3, 62.7; FT-IR(neat) ν 3435, 2929,
2858, 1736, 1473, 1464, 1254, 1111, 870, 779 cm-1; HRMS
J. Org. Chem, Vol. 70, No. 14, 2005 5649

Hayashi et al.
filtration. Purification by silica gel column chromatography
(diethyl ether/pentane ) 1:5) gave 458 mg (93%) of aldehyde
(-)-6 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.99 (3H,
t, J ) 7.5 Hz), 2.07-2.32 (2H, m), 3.25 (1H, dd, J ) 6.0, 1.5
Hz), 3.87 (1H, d, J ) 8.4 Hz), 4.96 (1H, dd, J ) 10.7. 9.2 Hz),
5.80 (1H, dt, Jd ) 10.7 Hz, Jt ) 7.5 Hz), 9.05 (1H, d, J ) 6.0
Hz); 13C NMR (100 MHz, CDCl3) δ 13.9, 21.1, 52.4, 60.4, 122.9,
140.8, 197.5; FT-IR (neat) ν 2968, 2935, 2875, 1728, 1668, 1633,
1066, 818, 735, 536 cm-1; HRMS (FAB) calcd for C7H10O2
H]+ calcd for C30H42O5NSi 524.2832, found 524.2824; [R]19
D
+98.8 (c 0.60, CHCl3).
(5S,8R,9R)-2-((1S,2R)-(Z)-1,2-epoxyhex-3-enyl)-8-hy-
droxy-8-(hydroxy-phenyl-methyl)-3-methyl-9-triisopro-
pylsiloxy-1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione (19).
To a MeOH solution (22.5 mL) of azaspiro[4.4]nonenedione 18
(197 mg, 0.376 mmol) was added an acetone solution of
dimethyl dioxirane (0.084 M, 45 mL, 3.76 mmol) at -60 °C,
and the reaction mixture was stirred for 16 h. The reaction
was quenched by the addition of Me2S (0.83 mL, 11.3 mmol)
and concentrated in vacuo after filtration. Purification by silica
gel column chromatography (ethyl acetate/hexane ) 1:9-1:4)
gave 84 mg (40%) of diol 19 as a colorless oil with the recovery
126.0681, found 126.0668; [R]21 -296.7 (c 1.04, CHCl3).
D
(3S,4S)-5-(Z)-Benzylidene-3-((4R,5R)-(Z)-4,5-epoxy-3-
hydroxy-2-methylnon-6-enoyl)-3-hydroxy-4-triisopropyl-
siloxypyrrolidin-2-one (17). To a THF solution (4.0 mL) of
diisopropylamine (0.75 mL, 5.30 mmol) and HMPA (0.90 mL,
5.17 mmol) was added a hexane solution of n-BuLi (2.4 M, 1.75
mL, 4.27 mmol) at 0 °C, and the reaction mixture was stirred
for 10 min. To the reaction mixture was added a THF solution
(4.0 mL) of ketone 7 (430 mg, 1.04 mmol) at -78 °C, and the
reaction mixture was stirred for 1.5 h. Aldehyde (-)-6 (380
mg, 3.02 mmol) was added to the reaction mixture at -78 °C,
and then the reaction temperature was raised to -50 °C over
1 h. The reaction was quenched by the addition of pH 7.0
phosphate buffer, and the organic materials were extracted
with ethyl acetate three times, dried over anhydrous Na2SO4,
and concentrated in vacuo after filtration. Purification by silica
gel column chromatography (diethyl ether/hexane ) 1:4, ethyl
acetate/hexane ) 1:4-1:3) gave 250 mg (45%) of a 2:1 diaster-
eomeric mixture of aldol 17 along with the recovery of the
ketone 7 (210 mg, 49%). A mixture of diastereomers was
employed in the next experiment, but careful TLC separated
the major isomer, which shows the following spectral data: 1H
NMR (400 MHz, CDCl3) δ 0.93 (3H, t, J ) 7.5 Hz), 1.05-1.21
(21H, m), 1.23 (3H, d, J ) 6.8 Hz), 1.96-2.20 (2H, m), 2.74
(1H, bs), 2.87 (1H, dd, J ) 2.2, 3.8 Hz), 3.28-3.41 (1H, m),
3.45 (1H, dd, J ) 9.0, 1.6 Hz), 3.65 (1H, bd, J ) 3.4 Hz), 4.77
(1H, s), 4.89 (1H, t, J ) 9.2 Hz), 5.17 (1H, d, J ) 1.6 Hz), 5.66
(1H, dt, Jd ) 10.8, Jt ) 7.7 Hz), 5.95 (1H, s), 7.18-7.39 (5H,
m), 8.77 (1H, bs); 13C NMR (100 MHz, CDCl3) δ 12.4, 12.6,
14.2, 17.8, 17.9, 21.6, 46.8, 52.1, 60.4, 71.6, 79.7, 88.5, 104.0,
124.7, 127.2, 127.5, 129.2, 134.6, 135.8, 139.2, 169.4, 205.8;
FT-IR (neat) ν 3417, 2945, 2870, 1747, 1684, 1452, 1134, 883,
816, 683 cm-1; HRMS (FAB) [M + H]+ calcd for C30H46O6NSi
544.3094, found 544.3071.
1
of 18 (66 mg, 33%): H NMR (400 MHz, CDCl3) δ 0.90-1.16
(24H, m), 1.75 (3H, s), 2.17-2.35 (2H, m), 2.51 (1H, bs), 3.75
(1H, s), 4.11 (1H, bd, J ) 6.9 Hz), 4.88 (1H, s), 5.06 (1H, t, J
) 9.8 Hz), 5.35 (1H, s), 5.74 (1H, s), 5.84 (1H, dt, Jd ) 10.8, Jt
) 7.7 Hz), 6.19 (1H, bs), 7.30-7.45 (5H, m); 13C NMR (100
MHz, CDCl3) δ 5.0, 12.6, 14.0, 17.8, 17.8, 21.3, 52.8, 55.0, 71.6,
71.7, 86.6, 94.7, 114.4, 123.6, 127.0, 128.5, 138.2, 141.3, 164.4,
183.2, 199.4; FT-IR (neat) ν 3348, 2943, 2870, 1736, 1693, 1624,
1458, 1196, 1068, 883, 825, 698 cm-1; HRMS (FAB) [M - OH]+
calcd for C30H42O6NSi 540.2781, found 540.2733; [R]19D -71.4
(c 0.46, CHCl3).
(5S,8S,9R)-8-Benzoyl-2-((1S,2R)-(Z)-1,2-epoxyhex-3-enyl)-
8-hydroxy-3-methyl-9-triisopropylsiloxy-1-oxa-7-azaspiro-
[4.4]nonene-4,6-dione (20). To a CH2Cl2 solution (0.73 mL)
of diol 19 (8.1 mg, 0.0146 mmol) and NaHCO3 (21 mg, 0.219
mmol) was added Dess-Martin periodinane (37 mg, 0.0871
mmol) at 0 °C. After 5 min, the reaction mixture was warmed
to room temperature and a solution of a mixture (0.29 mL,
0.0161 mmol) of CH2Cl2 and H2O (1000:1) was added. After
stirring the reaction mixture for 7.5 h at that temperature,
the reaction was quenched by the addition of saturated
aqueous NaHCO3 and diluted with ethyl acetate. The organic
materials were extracted with ethyl acetate three times, and
the combined organic extracts were washed with saturated
aqueous NaHCO3 twice, dried over anhydrous Na2SO4, and
concentrated in vacuo after filtration. Purification by silica gel
column chromatography (ethyl acetate/hexane ) 1:10-1:3)
gave 7.7 mg (95%) of benzoyl product 20 as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 0.94-1.01 (21H, m), 1.05 (3H, t, J
) 7.5 Hz), 1.81 (3H, s), 2.18-2.35 (2H, m), 3.77 (1H, bd, J )
1.8 Hz), 4.11 (1H, ddd, J ) 9.2, 1.8, 1.0 Hz), 5.08 (1H, bt, J )
10.8 Hz), 5.47 (1H, s), 5.86 (1H, dt, Jd ) 10.8 Hz, Jt ) 7.5 Hz),
6.40 (1H, s), 6.73 (1H, bs), 7.47 (2H, dd, J ) 7.8, 7.6 Hz), 7.61
(1H, bt, J ) 7.4 Hz), 8.31 (2H, bdd, J ) 8.1, 0.9 Hz); 13C NMR
(100 MHz, CDCl3) δ 5.1, 12.3, 14.0, 17.7, 21.3, 52.8, 55.1, 72.5,
88.2, 93.5, 114.4, 123.4, 128.7, 130.7, 132.9, 134.1, 141.5, 163.9,
183.4, 191.8, 199.3; FT-IR (neat) ν 3263, 2927, 2866, 1736,
1693, 1624, 1462, 1242, 1188, 1072, 883, 822, 687 cm-1; HRMS
(FAB): [M - OH]+ calcd for C30H40O6NSi 538.2625, found
(5S,9S)-8-(Z)-Benzylidene-2-((1S,2R)-(Z)-1,2-epoxyhex-
3-enyl)-3-methyl-9-triisopropylsiloxy-1-oxa-7-azaspiro-
[4.4]non-2-ene-4,6-dione (18). To a CH2Cl2 solution (12.2 mL)
of a mixture of diastereomer of aldol 17 (250 mg, 0.462 mmol)
and NaHCO3 (356 mg, 4.24 mmol) was added Dess-Martin
periodinane (494 mg, 1.16 mmol) at 0 °C. After 5 min, the
reaction mixture was warmed to room temperature and a
solution of a mixture (9.1 mL, 0.508 mmol) of CH2Cl2 and H2O
(1000:1) was added. After stirring the reaction mixture for 1
h at that temperature, the reaction was quenched by the
addition of saturated NaHCO3 and diluted with ethyl acetate.
The organic materials were extracted with ethyl acetate three
times, and the combined organic extracts were washed with
saturated NaHCO3 twice, dried over anhydrous Na2SO4, and
concentrated in vacuo after filtration. Crude organic materials
were charged on the TLC and were left for 20 min. After
extraction of the organic materials from silica gel, the crude
materials were purified by silica gel column chromatography
(ethyl acetate/hexane ) 1:5-1:2), affording 178 mg (47%) of
538.2652; [R]21 -50.1 (c 0.77, CHCl3).
D
(5S,8S,9R)-8-Benzoyl-2-((1S,2R)-(Z)-1,2-epoxyhex-3-enyl)-
8-hydroxy-3-methyl-6,9-bis-triisopropylsilanyloxy-1-oxa-
7-azaspiro[4.4]nona-2,6-dien-4-one (21). To a CH2Cl2 so-
lution (0.35 mL) of 20 (10.5 mg, 0.0190 mmol) was added 2,6-
lutidine (0.015 mL, 0.129 mmol) and TIPSOTf (0.015 mL,
0.0569 mmol) at 0 °C. After stiiring the reaction mixture for
30 min at that temperature, the reaction was quenched by the
addition of cold saturated NaHCO3, and the organic materials
were extracted with ethyl acetate three times, dried over
anhydrous Na2SO4, and concentrated in vacuo after filtration.
As 21 was labile, it was purified by a very short column of
florisil in a short time and was immediately used in the next
experiment: 1H NMR (400 MHz, CDCl3) δ 0.90-1.09 (42H,
m), 1.80 (3H, s), 2.15-2.33 (2H, m), 3.74 (1H, bd, J ) 1.7 Hz),
4.04 (1H, bdd, J ) 7.0, 1.0 Hz), 5.08 (1H, bt, J ) 9.1 Hz), 5.17
(1H, s), 5.69 (1H, s), 5.85 (1H, dt, Jd ) 11.0 Hz, Jt ) 7.6 Hz),
7.40 (2H, t, J ) 7.8 Hz), 7.50 (1H, t, J ) 7.4 Hz), 8.28 (2H, d,
J ) 7.7 Hz); FT-IR (neat) ν 3460, 2943, 2867, 1701, 1633, 1464,
1
azaspiro[4.4]nonenedione 18 as a colorless oil: H NMR (400
MHz, CDCl3) δ 1.00-1.16 (24H, m), 1.77 (3H, s), 2.14-2.37
(2H, m), 3.76 (1H, s), 4.11 (1H, d, J ) 8.8 Hz), 5.08 (1H, dd, J
) 10.5, 8.8 Hz), 5.41 (1H, s), 5.84 (1H, dt, 10.5, 7.8 Hz), 7.13-
7.36 (5H, m), 8.00 (1H, bs); 13C NMR (100 MHz, CDCl3) δ 5.1,
12.7, 14.0, 17.8, 17.9, 21.3, 29.7, 52.8, 54.7, 75.1, 92.3, 104.4,
114.4, 123.7, 126.9, 127.7, 128.9, 134.2, 134.9, 141.2, 164.8,
180.4, 194.9; FT-IR (neat) ν 3255, 2945, 2868, 1743, 1712, 1695,
1641, 1452, 1186, 1140, 1070, 883 cm-1; HRMS (FAB) [M +
1383, 1367, 1252, 1186, 1051, 804, 677 cm-1
.
5650 J. Org. Chem., Vol. 70, No. 14, 2005

Asymmetric Total Synthesis of Synerazol
(5S,8S,9R)-8-Benzoyl-2-((1S,2R)-(Z)-1,2-epoxyhex-3-enyl)-
8-methoxy-3-methyl-9-triisopropylsioxy-1-oxa-7-azaspiro-
[4.4]non-2-ene-4,6-dione (22). A MeCN solution (0.45 mL)
of 21 (13.5 mg, 0.0190 mmol) and MS4A (27 mg, 200 wt %)
was stirred for 1.5 h at room temperature, and then to the
reaction mixture were added Ag2O (618 mg, 2.05 mmol) and
MeI (0.09 mL, 1.57 mmol) at that temperature in the dark.
After 40 min, the reaction mixture was filtered through a pad
of Celite, and the volatile organic materials were removed
under reduced pressure. Purification by thin-layer chroma-
tography (ethyl acetate/hexane ) 1:3) gave 1.1 mg (10%) of
methyl ether 22 and alcohol 20 (3.7 mg, 35%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 0.88-1.05 (24H, m), 1.79 (3H,
s), 2.14-2.34 (2H, m), 3.62 (1H, bs), 3.74 (3H, s), 4.06 (1H,
ddd, J ) 8.8, 2.0, 0.9 Hz), 5.05 (1H, bdd, J ) 10.3, 9.6 Hz),
5.47 (1H, s), 5.82 (1H, dt, Jd ) 10.2, Jt ) 7.6 Hz), 6.66 (1H,
bs), 7.46 (2H, t, J ) 7.3 Hz), 7.60 (1H, bt, J ) 7.4 Hz), 8.16
(2H, bdd, J ) 7.4, 0.9 Hz); 13C NMR (100 MHz, CDCl3) δ 5.2,
12.6, 14.0, 17.7, 21.3, 52.3, 52.7, 54.6, 75.2, 91.4, 115.0, 123.6,
128.9, 130.4, 133.2, 134.1, 141.3, 166.2, 179.8, 192.9, 195.3;
FT-IR (neat) ν 2927, 2868, 1734, 1712, 1645, 1464, 1238, 1182,
1090, 1039, 883, 687; HRMS (FAB) [M + H]+ calcd for
12.8, 14.7, 18.2, 18.3, 21.5, 45.5, 52.3, 60.5, 69.7, 80.1, 88.5,
104.7, 125.3, 127.6, 127.9, 129.5, 135.0, 136.4, 139.9, 170.0,
205.7; IR (neat) ν 3440, 2964, 2945, 2870, 1740, 1693, 1454,
1363, 1182, 1136, 1012, 883, 816, 683 cm-1; HRMS (FAB) [M
+ H]+ calcd for C30H46O6NSi 544.3094, found 544.3098.
(5S,9S)-8-(Z)-Benzylidene-2-((1R,1S)-(Z)-1,2-epoxyhex-
3-enyl)-3-methyl-9-triisopropylsiloxy-1-oxa-7-azaspiro-
[4.4]non-2-ene-4,6-dione (27). To a CH2Cl2 solution (3.8 mL)
of a mixture of the diastereomer of aldol 26 (58 mg, 0.107
mmol) and NaHCO3 (93 mg, 1.11 mmol) was added Dess-
Martin periodinane (156 mg, 0.367 mmol) at 0 °C. After 5 min,
the reaction mixture was warmed to room temperature and a
solution of a mixture (2.1 mL, 0.118 mmol) of CH2Cl2 and H2O
(1000:1) was added. After stirring the reaction mixture for 1
h at that temperature, the reaction was quenched by the
addition of saturated aqueous NaHCO3 and diluted with ethyl
acetate. The organic materials were extracted with ethyl
acetate three times, and the combined organic extracts were
washed with saturated NaHCO3 twice, dried over anhydrous
Na2SO4, and concentrated in vacuo after filtration. Purification
by silica gel column chromatography (ethyl acetate/hexane )
1:5-1:2) gave 26 mg (38%) of azaspiro[4.4]nonenedione 27 as
C31H44O7NSi 570.2887, found 570.2861; [R]22 -26.2 (c 0.23,
1
D
a colorless oil: H NMR (400 MHz, CDCl3) δ 1.03-1.13 (24H,
CHCl3).
m), 1.77 (3H, s), 2.14-2.35 (2H, m), 3.73 (1H, bd, J ) 9.5 Hz),
4.11 (1H, bd, J ) 9.0 Hz), 5.09 (1H, bt, J ) 10.5 Hz), 5.43 (1H,
bd, J ) 1.7 Hz), 5.86 (1H, bdt, Jd ) 11.0, Jt ) 7.5 Hz), 5.94
(1H, s), 7.18-7.39 (5H, m), 7.79 (1H, bs); 13C NMR (100 MHz,
CDCl3) δ 5.1, 12.7, 14.1, 17.8, 17.9, 21.3, 53.3, 54.6, 75.0, 92.3,
104.4, 114.3, 123.6, 127.0, 129.0, 134.1, 134.9, 141.2, 164.6,
180.3, 195.0; FT-IR (neat) ν 3273, 2943, 2868, 1743, 1714, 1695,
1645, 1456, 1186, 1068, 883, 812, 685 cm-1; HRMS (FAB) [M
(+)-Synerazol. To a MeOH solution (0.1 mL) of methyl
ether 22 (1.0 mg, 0.00176 mmol) was added NH4F (2.2 mg,
0.0594 mmol) at 0 °C. After 1 h, the reaction mixture was
warmed to room temperature and stirred for 11 h at that
temperature, the volatile organic materials were removed
under reduced pressure, and purification by thin-layer chro-
matography (ethyl acetate/hexane ) 1:1) gave 0.4 mg (55%)
of synerazol with the recovery of 22 (0.3 mg, 30%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 1.02 (3H, t, J ) 7.5 Hz), 1.81
(3H, s), 2.17-2.35 (2H, m), 3.37 (3H, s), 3.74 (1H, bd, J ) 1.7
Hz), 4.01 (1H, bd, J ) 12.1 Hz), 4.08 (1H, bddd, J ) 9.0, 1.7,
1.0 Hz), 4.62 (1H, d, J ) 11.9 Hz), 5.06 (1H, bdd, J ) 10.9, 9.0
Hz), 5.83 (1H, bdt, Jd ) 11.0, Jt ) 7.6 Hz), 7.28 (1H, bs), 7.46
(2H, t, J ) 7.6 Hz), 7.62 (1H, bt, J ) 7.4 Hz), 8.25 (2H, bdd, J
) 8.6, 1.3 Hz); 13C NMR (150 MHz, CDCl3) δ 5.2, 14.0, 21.3,
51.7, 52.6, 55.1, 73.8, 89.4, 91.8, 114.3, 123.5, 128.7, 130.5,
132.2, 134.7, 141.5, 165.1, 182.1, 194.3, 196.7; FT-IR (neat) ν
3475, 3261, 2925, 1738, 1705, 1631, 1107, 1024, 791; HRMS
(FAB) [M + H]+ calcd for C22H24O7N 414.1553, found 414.1537;
+ H]+ calcd for C30H42O5NSi 524.2832, found 524.2799; [R]32
+79 (c 0.61, CHCl3).
D
(5S,8R,9R)-2-((1R,2S)-(Z)-1,2-Epoxyhex-3-enyl)-8-hy-
droxy-8-(hydroxy-phenyl-methyl)-3-methyl-9-triisopro-
pylsiloxy-1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione (28).
To a MeOH solution (9.5 mL) of azaspiro[4.4]nonenedione 27
(134 mg, 0.180 mmol) was added an acetone solution of
dimethyl dioxirane (0.094 M, 19 mL, 1.80 mmol) at -60 °C,
and the reaction mixture was stirred for 14 h. The reaction
was quenched by the addition of Me2S (0.45 mL, 6.13 mmol)
and concentrated in vacuo after filtration. Purification by silica
gel column chromatography (ethyl acetate/hexane ) 1:9-1:4)
gave 66 mg (46%) of diol 28 as a colorless oil with the recovery
[R]22 +22.6 (c 0.14, CHCl3).
D
1
of 27 (60 mg, 45%): H NMR (400 MHz, CDCl3) δ 1.00-1.19
(3S,4S)-5-(Z)-Benzylidene-3-((4S,5S)-(Z)-4,5-epoxy-3-
hydroxy-2-methylnon-6-enoyl)-3-hydroxy-4-triisopropyl-
siloxy-pyrrolidin-2-one (26). To a THF solution (5.0 mL) of
diisopropylamine (0.95 mL, 6.71 mmol) and HMPA (1.15 mL,
6.71 mmol) was added a hexane solution of n-BuLi (2.44 M,
2.3 mL, 5.61 mmol) at 0 °C, and the reaction mixture was
stirred for 10 min. To the reaction mixture was added a THF
solution (5.0 mL) of ketone 7 (557 mg, 1.34 mmol) at -78 °C,
and the reaction mixture was stirred for 1.5 h. Aldehyde (+)-6
(415 mg, 3.30 mmol) was added to the reaction mixture at -78
°C, and then the reaction temperature was raised to -55 °C
over 1 h. The reaction was quenched by the addition of pH 7.0
phosphate buffer, and the organic materials were extracted
with ethyl acetate three times, dried over anhydrous Na2SO4,
and concentrated in vacuo after filtration. Purification by silica
gel column chromatography (diethyl ether/hexane ) 1:4, ethyl
acetate/hexane ) 1:4-1:3) gave 235 mg (33%) of a 2:1 diaster-
eomeric mixture of aldol 26 as a colorless oil along with the
recovery of the ketone 7 (317 mg, 57%). A mixture of diaster-
eomers was employed in the next reaction, but careful TLC
separated the major isomer, which shows the following spectral
(24H, m), 1.76 (3H, s), 2.13-2.36 (3H, m), 3.74 (1H, bd, J )
1.2 Hz), 4.10 (1H, bd, J ) 8.7 Hz), 4.91 (1H, bs), 5.09 (1H, bt,
J ) 10.3 Hz), 5.39 (1H, s), 5.74 (1H, s), 5.77 (1H, s), 5.87 (1H,
dt, Jd ) 10.8, Jt ) 7.7 Hz), 6.13 (1H, bs), 7.31-7.50 (5H, m);
13C NMR (100 MHz, CDCl3) δ 5.1, 12.7, 14.1, 17.8, 21.3, 53.1,
55.0, 71.5, 71.7, 86.5, 94.8, 114.2, 123.6, 126.9, 128.6, 128.8,
138.1, 141.3, 164.0, 183.0, 199.3; FT-IR (neat) ν 3381, 2945,
2868, 1736, 1693, 1626, 1464, 1456, 1194, 1068, 883, 813 cm-1
;
HRMS (FAB) [M + H]+ calcd for C30H44O7NSi 558.2887, found
558.2875; [R]21 -84.5 (c 0.43, CHCl3).
D
(5S,8S,9R)-8-Benzoyl-2-((1R,2S)-(Z)-1,2-epoxyhex-3-enyl)-
8-hydroxy-3-methyl-9-triisopropylsiloxy-1-oxa-7-azaspiro-
[4.4]nonene-4,6-dione (29). To a CH2Cl2 solution (2.6 mL)
of diol 28 (29 mg, 0.0522 mmol) and NaHCO3 (100 mg, 1.19
mmol) was added Dess-Martin periodinane (159 mg, 0.374
mmol) at 0 °C. After 5 min, to the reaction mixture was added
to a solution of a mixture (1.0 mL, 0.0574 mmol) of CH2Cl2
and H2O (1000:1). After stirring the reaction mixture for 6 h
at that temperature, the reaction was quenched by the addition
of saturated aqueous NaHCO3 and diluted with ethyl acetate.
The organic materials were extracted with ethyl acetate three
times, and the combined organic extracts were washed with
saturated aqueous NaHCO3 twice, dried over anhydrous
Na2SO4, and concentrated in vacuo after filtration. Purification
by silica gel column chromatography (ethyl acetate/hexane )
1:9-1:2) gave 24.8 mg (90%) of benzoyl product 29 as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.91-1.07 (24H,
1
data: H NMR (400 MHz, CDCl3) δ 0.90 (3H, t, J ) 7.5 Hz),
0.93-1.06 (21H, m), 1.09 (3H, d, J ) 7.0 Hz), 2.02-2.15 (2H,
m), 2.74 (1H, bt, J ) 2.4 Hz), 2.90 (1H, bs), 3.24-3.37 (1H,
m), 3.55 (1H, bd, J ) 9.3 Hz), 3.76 (1H, bs), 4.73 (1H, s), 4.82
(1H, dd, J ) 10.6, 9.4 Hz), 5.01 (1H, bd, J ) 1.9 Hz), 5.61 (1H,
dt, Jd ) 10.9, Jt ) 7.6 Hz), 5.87 (1H, bd, J ) 1.9 Hz), 7.06-
7.29 (5H, m), 8.56 (1H, bs); 13C NMR (100 MHz, CDCl3) δ 10.8,
J. Org. Chem, Vol. 70, No. 14, 2005 5651

Hayashi et al.
m), 1.81 (3H, bd, J ) 0.9 Hz), 2.10-2.36 (2H, m), 3.75 (1H,
bs), 4.11 (1H, bd, J ) 8.8 Hz), 5.09 (1H, bt, J ) 9.5 Hz), 5.52
(1H, s), 5.87 (1H, bdt, Jd ) 10.1 Hz, Jt ) 8.2 Hz), 6.38 (1H, s),
6.76 (1H, bs), 7.48 (2H, t, J ) 7.0 Hz), 7.61 (1H, bt, J ) 6.8
Hz), 8.29 (2H, bd, J ) 7.9 Hz); 13C NMR (100 MHz, CDCl3) δ
5.0, 12.3, 14.1, 17.7, 21.3, 53.0, 55.0, 72.3, 88.1, 93.5, 114.2,
123.5, 128.7, 130.6, 132.8, 134.1, 141.4, 164.0, 183.6, 191.6,
199.3; FT-IR (neat) ν 3290, 2943, 2868, 1747, 1739, 1693, 1626,
1464, 1240, 1186, 1072, 883, 685 cm-1; HRMS (FAB) [M + H]+
calcd for C30H42O7NSi 556.2731, found 556.2733; [R]22D -81.4
(c 0.19, CHCl3).
(5S,8S,9R)-8-Benzoyl-2-((1R,2S)-(Z)-1,2-epoxyhex-3-enyl)-
8-hydroxy-3-methyl-6,9-bis-triisopropylsiloxy-1-oxa-7-
azaspiro[4.4]nona-2,6-dien-4-one (30). To a CH2Cl2 solu-
tion (0.47 mL) of 29 (9.6 mg, 0.0173 mmol) were added 2,6-
lutidine (0.015 mL, 0.129 mmol) and TIPSOTf (0.015 mL,
0.0558 mmol) at 0 °C. After stirring the reaction mixture for
30 min at that temperature, the reaction was quenched by the
addition of cold saturated aqueous NaHCO3, and the organic
materials were extracted with ethyl acetate three times, dried
over anhydrous Na2SO4, and concentrated in vacuo after
filtration. As 30 was labile, it was purified by a very short
column of florisil in a short time and was immediately used
in the next experiment: 1H NMR (400 MHz, CDCl3) δ 0.90-
1.09 (42H, m), 1.80 (3H, s), 2.17-2.35 (2H, m), 3.74 (1H, bd, J
) 1.4 Hz), 4.08 (1H, bd, J ) 8.0 Hz), 5.09 (1H, bt, J ) 9.5 Hz),
5.21 (1H, s), 5.70 (1H, s), 5.86 (1H, dt, Jd ) 11.0 Hz, Jt ) 7.7
Hz), 7.41 (2H, t, J ) 7.7 Hz), 7.51 (1H, t, J ) 7.3 Hz), 8.28
(2H, d, J ) 7.6 Hz).
(5S,8S,9R)-8-Benzoyl-2-((1R,2S)-(Z)-1,2-epoxyhex-3-enyl)-
8-methoxy-3-methyl-9-triisopropylsiloxy-1-oxa-7-azaspiro-
[4.4]non-2-ene-4,6-dione (31). A MeCN solution (0.3 mL) of
30 (12 mg, 0.0169 mmol) and MS4A (24 mg, 200 wt %) was
stirred for 1.5 h at room temperature, and then to the reaction
mixture were added Ag2O (508 mg, 1.69 mmol) and MeI (0.048
mL, 0.843 mmol) at that temperature in the dark. After 40
min, the reaction mixture was filtered through a pad of Celite,
and the volatile organic materials were removed under reduced
pressure. Purification by thin-layer chromatography (ethyl
acetate/hexane ) 1:3) gave 1.0 mg (10%) of methyl ether 31
as a colorless oil along and alcohol 29 (3.0 mg, 32%).
quenched by the addition of pH 7.0 phosphate buffer, and the
organic materials were extracted with chloroform three times,
dried over anhydrous Na2SO4, and concentrated in vacuo after
filtration. Purification by thin-layer chromatography (ethyl
acetate/hexane ) 1:1) gave 44 mg (92%) of diol 40 as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 1.00 (3H, bt, J ) 7.0 Hz),
2.49 (1H, bdq, Jd ) 19.0, Jq ) 7.0 Hz), 2.73 (1H, bdq, Jd
)
19.0, Jq ) 7.1 Hz), 4.24 (1H, bs), 4.99 (1H, s), 5.16 (1H, bs),
5.92 (1H, s), 7.17-7.32 (5H, m), 8.64 (1H, bs); 13C NMR (100
MHz, CDCl3) δ 6.9, 32.1, 77.8, 86.9, 104.9, 127.1, 127.5, 129.0,
134.63, 134.65, 171.3, 205.2; FT-IR (neat) ν 3336, 2925, 1736,
1718, 1689, 1404, 1381, 1174, 1115, 956, 908, 758, 694, 644
cm-1; HRMS (FAB) [M + H]+ calcd for C14H16NO4 262.1079,
found 262.1099; [R]23 +203 (c 0.35, CHCl3).
D
(3S,4S)-5-(Z)-Benzylidene-3-hydroxy-3-propyonyl-4-
trimethylsilanyloxy-pyrrolidin-2-one (42). To a DMF solu-
tion (0.5 mL) of diol 40 (12 mg, 0.0459 mmol) and imidazole
(15.6 mg, 0.0230 mmol) was added TMSCl (10 µL, 0.081 mmol)
at -78 °C. After stirring for 5 min at that temperature, the
reaction was quenched by the addition of pH 7.0 phosphate
buffer, the organic materials were extracted with ethyl acetate
three times, and the combined organic extracts were washed
with brine three times, dried over anhydrous Na2SO4, and
concentrated in vacuo after filtration. Purification by thin-layer
chromatography (ethyl acetate/hexane ) 1:2) gave 12.7 mg
(83%) of ketone 42 as a colorless oil. Enantiomeric excess was
determined as >99.5% by chiral HPLC analysis [HPLC condi-
tions: Chiralpak AS-H column, 2-propanol/hexane ) 1:20, 1.0
mL/min, retention times, 10.51 min (major), 8.12 min (minor)]:
1H NMR (400 MHz, CDCl3) δ 0.07 (9H, s), 0.98 (3H, t, J )
7.1 Hz), 2.33 (1H, dq, Jd ) 18.5, Jq ) 7.1 Hz), 2.66 (1H, dq, Jd
) 18.5, Jq ) 7.1 Hz), 4.59 (1H,s), 4.88 (1H, bd, J ) 2.0 Hz),
5.68 (1H, bd, J ) 1.6 Hz), 7.14-7.30 (5H, m), 7.90 (1H, bs);
13C NMR (100 MHz, CDCl3) δ -0.094, 7.0, 31.6, 78.4, 86.4,
103.9, 127.1, 127.4, 129.1, 134.7, 135.7, 170.3, 203.6; FT-IR
(neat) ν 3448, 3265, 2966, 1747, 1732, 1691, 1354, 1254, 1136,
881, 846, 754, 694 cm-1; HRMS (FAB) [M + H]+ calcd for
C17H24O4NSi 334.1475, found 334.1498; [R]22 +204 (c 0.35,
D
CHCl3).
(3S,4S)-5-(Z)-Benzylidene-3-((4R,5R)-(Z)-4,5-epoxy-3-
hydroxy-2-methylnon-6-enoyl)-3-hydroxy-4-trimethylsi-
loxypyrrolidin-2-one (44). To a THF solution (0.68 mL) of
diisopropylamine (0.1 mL, 0.707 mmol) and HMPA (0.11 mL,
0.608 mmol) was added a hexane solution of n-BuLi (1.51 M,
0.37 mL, 0.554 mmol) at 0 °C, and the reaction mixture was
stirred for 10 min. To the reaction mixture was added a THF
solution (1.2 mL) of ketone 42 (45 mg, 0.135 mmol) at -78 °C,
and the reaction mixture was stirred for 1 h. Aldehyde (-)-6
(92 mg, 0.730 mmol) was added to the reaction mixture at -78
°C, and then the reaction temperature was raised to -50 °C
over 1 h. The reaction was quenched by the addition of pH 7.0
phosphate buffer, and the organic materials were extracted
with chloroform three times, dried over anhydrous Na2SO4,
and concentrated in vacuo after filtration. Purification by silica
gel column chromatography (diethyl ether/hexane )1:4) gave
20 mg (32%) of a 2:1 diastereomeric mixture of aldol 44 as a
colorless oil along with the recovery of the ketone 42 (22 mg,
49%) and 5.3 mg (15%) of diol 40. A mixture of diastereomers
was employed in the next reaction, but careful TLC separated
the major isomer, which shows the following spectral data: 1H
NMR (400 MHz, CDCl3) δ 0.19 (9H, s), 0.954 (3H, t, J ) 7.4
Hz), 1.21 (3H, d, J ) 6.7 Hz), 2.01-2.27 (2H, m), 2.90 (1H, s),
3.29 (1H, quint, J ) 6.2 Hz), 3.51 (1H, d, J ) 8.9 Hz), 3.67
(1H, bs), 4.75 (1H, bs, 4.92 (1H, t, J ) 9.8 Hz), 4.97 (1H, s),
5.68 (1H, dt, Jd ) 10.4, Jt ) 7.9 Hz), 5.75 (1H, s), 7.21-7.37
(5H, m), 8.47 (1H, bs); 13C NMR (100 MHz, CDCl3) δ -0.1,
12.5, 14.2, 21.0, 46.9, 52.0, 60.2, 71.3, 79.0, 88.0, 103.6, 124.7,
127.1, 127.4, 129.1, 134.7, 135.6, 139.4, 169.5, 206.4; FT-IR
(neat) ν 3423, 2962, 1735, 1689, 1456, 1373, 1254, 1182, 1136,
876, 847, 754, 694 cm-1; HRMS (FAB) [M + H]+ calcd for
(5S,8S,9R)-8-Benzoyl-2-((1R,2S)-(Z)-1,2-epoxyhex-3-enyl)-
9-hydroxy-8-methoxy-3-methyl-1-oxa-7-azaspiro[4.4]non-
2-ene-4,6-dione (5). To a MeOH solution (0.1 mL) of methyl
ether 31 (1 mg, 0.00176 mmol) was added NH4F (3 mg, 0.081
mmol) at 0 °C. After 1 h, the reaction mixture was warmed to
room temperature and stirred for 8.5 h at that temperature,
the volatile organic materials were removed under reduced
pressure, and purification by thin-layer chromatography (ethyl
acetate/hexane ) 1:1) gave 0.2 mg (30%) of 5 as a colorless oil
with the recovery of 31 (0.3 mg, 30%): [R]22 -49.2 (c 0.02,
D
CHCl3).
(4S,5R,8R,9R)-4-Ethyl-8-(hydroxyphenylmethyl)-8-meth-
oxy-2,2-dimethyl-9-triisopropylsilanyloxy-1,3-dioxa-7-
azaspiro[4.4]nonan-6-one (33). To a MeOH solution (19 mL)
of lactam 32 (85 mg, 0.185 mmol) was added an acetone
solution of dimethyl dioxirane (0.1 M, 9.5 mL, 0.925 mmol) at
-60 °C, and the reaction mixture was stirred for 6 h. The
reaction was quenched by the addition of Me2S (0.2 mL, 2.78
mmol) and concentrated in vacuo after filtration. Purification
by thin-layer chromatography (ethyl acetate/hexane ) 1:3)
gave 87 mg (93%) of methyl ether 33 as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 1.05 (3Η, t, J ) 7.2 Hz), 1.13-1.22
(21H, m), 1.25-1.35 (2H, m), 1.46 (3H, s), 1.61 (3H, s), 3.23
(3H, s), 3.31 (1H, d, J ) 6.5 Hz), 4.35 (1H, bdd, J ) 11.1 Hz,
1.9 Hz), 4.84 (1H, d, J ) 6.4 Hz), 4.93 (1H, s), 5.23 (1H, bs),
7.28-7.39 (5H, m).
(3S,4S)-5-(Z)-Benzylidene-3,4-dihydroxy-3-propyo-
nylpyrrolidin-2-one (40). To a THF solution (2.0 mL) of the
ketone 7 (76 mg, 0.183 mmol) was added THF solution of
TBAF (1 M, 0.37 mL, 0.366 mmol) at -30 °C. After stirring
for 72 h at that temperature, the reaction mixture was
C24H34O6NSi 460.2155, found 460.2155; [R]19 +168 (c 0.79,
D
CHCl3).
5652 J. Org. Chem., Vol. 70, No. 14, 2005

Asymmetric Total Synthesis of Synerazol
(5S,9S)-8-(Z)-Benzylidene-2-((1S,2R)-(Z)-1,2-epoxyhex-
3-enyl)-3-methyl-9-trimethylsiloxy-1-oxa-7-azaspiro[4.4]-
non-2-ene-4,6-dione (46). To a CH2Cl2 solution (0.63 mL) of
a mixture of diastereomer of aldol 44 (7.0 mg, 0.0152 mmol)
and NaHCO3 (25 mg, 0.300 mmol) was added Dess-Martin
periodinane (39 mg, 0.0914 mmol) at 0 °C. After 5 min, the
reaction mixture was warmed to room temperature and added
to a solution of a mixture (0.3 mL, 0.0167 mmol) of CH2Cl2
and H2O (1000:1). After stirring for 30 min at that tempera-
ture, the reaction was quenched by the addition of saturated
aqueous NaHCO3 and diluted with ethyl acetate. The organic
materials were extracted with ethyl acetate three times, and
the combined organic extracts were washed with saturated
aqueous NaHCO3 twice, dried over anhydrous Na2SO4, and
concentrated in vacuo after filtration. Purification by thin-layer
chromatography (ethyl acetate/hexane ) 1:2) gave 3.5 mg
(52%) of azaspiro[4.4]nonenedione 46 as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 0.17 (9H, s), 1.04 (3H, t, J ) 7.5
Hz), 1.80 (3H, s), 2.20-2.35 (2H, m), 3.79 (1H, bd, J ) 1.9
Hz), 4.17 (1H, ddd, J ) 9.0, 1.9, 1.0 Hz), 5.08 (1H, dd, J )
10.7, 9.4 Hz), 5.20 (1H, bd, J ) 1.9 Hz), 5.80 (1H, bd, J ) 1.9
Hz), 5.85 (1H, dt, Jd ) 11.0, Jt ) 7.4 Hz), 7.19-7.27 (3H, m),
7.35 (2H, t, J ) 7.5 Hz), 7.76 (1H, bs); 13C NMR (100 MHz,
CDCl3) δ -0.1, 5.0, 14.1, 21.4, 52.6, 54.9, 74.5, 91.8, 104.0,
114.5, 123.7, 127.1, 127.7, 129.4, 134.0, 135.0, 141.3, 164.7,
180.4, 195.4; FT-IR (neat) ν 3265, 2962, 2852, 1739, 1714, 1697,
(1H, dd, J ) 10.1, 9.8 Hz), 5.83 (1H, dt, Jd ) 10.9, Jt ) 7.6
Hz), 7.08 (1H, bs), 7.45 (2H, t, J ) 7.8 Hz), 7.62 (1H, bt, J )
7.6 Hz), 8.37 (2H, d, J ) 7.4 Hz); 13C NMR (150 MHz, CDCl3)
δ -0.3, 5.2, 14.1, 14.1, 21.3, 51.9, 52.4, 54.8, 75.3, 91.9, 115.5,
123.6, 128.7, 131.3, 133.0, 134.6, 141.4, 165.3, 179.5, 194.7,
194.8; FT-IR (neat) ν 3294, 2960, 2925, 2852, 1743, 1716, 1685,
1645, 1448, 1254, 1142, 872, 850 cm-1; HRMS (FAB) [M + H]+
calcd for C25H32O7NSi 486.1948, found 486.1925; [R]30D +12.5
(c 0.15, CHCl3).
(+)-Synerazol. To a MeOH solution (0.2 mL) of benzoyl
product 48 (1.8 mg, 0.0037 mmol) was added NH4F (2.2 mg,
0.0594 mmol) at 0 °C. After stirring for 15 min, the volatile
organic materials were removed under reduced pressure, and
purification by thin-layer chromatography (ethyl acetate/
hexane ) 1:1) gave 1.5 mg (95%) of synerazol as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 1.02 (3H, t, J ) 7.5 Hz), 1.81
(3H, s), 2.17-2.35 (2H, m), 3.37 (3H, s), 3.74 (1H, bd, J ) 1.7
Hz), 4.01 (1H, bd, J ) 12.1 Hz), 4.08 (1H, bddd, J ) 9.0, 1.7,
1.0 Hz), 4.62 (1H, d, J ) 11.9 Hz), 5.06 (1H, bdd, J ) 10.9, 9.0
Hz), 5.83 (1H, bdt, Jd ) 11.0, Jt ) 7.6 Hz), 7.28 (1H, bs), 7.46
(2H, t, J ) 7.6 Hz), 7.62 (1H, bt, J ) 7.4 Hz), 8.25 (2H, bdd, J
) 8.6, 1.3 Hz); 13C NMR (150 MHz, CDCl3) δ 5.2, 14.0, 21.3,
51.7, 52.6, 55.1, 73.8, 89.4, 91.8, 114.3, 123.5, 128.7, 130.5,
132.2, 134.7, 141.5, 165.1, 182.1, 194.3, 196.7; FT-IR (neat) ν
3475, 3261, 2925, 1738, 1705, 1631, 1107, 1024, 791 cm-1
;
HRMS (FAB) [M + H]+ calcd for C22H24O7N 414.1553, found
1637, 1448, 1254, 1184, 1136, 1068, 879, 847, 752, 696 cm-1
;
414.1537; [R]22 +22.6 (c 0.14, CHCl3).
D
HRMS (FAB) [M + H]+ calcd for C24H30O5NSi 440.1893, found
(5S,8R,9R)-2-((1S,2R)-(Z)-1,2-Epoxyhex-3-enyl)-8-(hy-
droxy-phenyl-methyl)-8-methoxy-3-methyl-9-triethylsi-
loxy-1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione (45A). To a
MeOH solution (0.72 mL) of azaspiro[4.4]nonenedione 45 (3.5
mg, 0.00727 mmol) were added MS3A (12 mg) and an acetone
solution of dimethyl dioxirane (0.1 M, 0.36 mL, 0.0363 mmol)
at -60 °C, and the reaction mixture was stirred for 4 h. The
reaction was quenched by the addition of Me2S (0.02 mL, 0.272
mmol) and concentrated in vacuo after filtration. Purification
by thin-layer chromatography (ethyl acetate/hexane ) 1:2)
gave 1.2 mg (30%) of methyl ether 45A and 1.1 mg (30%) of
diol 45B with the recovery of 45 (1.0 mg, 30%).
440.1893; [R]19 +165 (c 0.22, CHCl3).
D
(5S,8R,9R)-2-((1S,2R)-(Z)-1,2-Epoxyhex-3-enyl)-8-(hy-
droxy-phenyl-methyl)-8-methoxy-3-methyl-9-trimethyl-
siloxy-1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione (47). To
a MeOH solution (0.7 mL) of azaspiro[4.4]nonenedione 46 (3.1
mg, 0.00705 mmol) was added MS3A (12 mg) and an acetone
solution of dimethyl dioxirane (0.1 M, 0.35 mL, 0.0353 mmol)
at -60 °C, and the reaction mixture was stirred for 4 h. The
reaction was quenched by the addition of Me2S (0.02 mL, 0.272
mmol) and concentrated in vacuo after filtration. Purification
by thin-layer chromatography (ethyl acetate/hexane ) 1:2)
gave 2.2 mg (65%) of methyl ether 47 as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ -0.03 (9H, s), 1.04 (3H, t, J ) 7.4
Hz), 1.76 (3H, s), 2.18-2.35 (2H, m), 3.51 (3H, m), 3.62 (1H,
bs), 3.73(1H, bd, J ) 1.8 Hz), 4.07 (1H, ddd, J ) 8.2, 1.8, 1.0
Hz), 4.65 (1H, bs), 4.90 (1H, s), 5.06 (1H, bt, J ) 9.9 Hz), 5.83
(1H, dt, Jd ) 11.1, Jt ) 7.5 Hz), 6.17 (1H, bs), 7.33-7.45 (5H,
m); 13C NMR (150 MHz, CDCl3) δ 0.26, 5.1, 14.1, 21.3, 52.6,
52.6, 54.7, 74.9, 76.3, 89.8, 91.7, 114.7, 123.7, 127.8, 128.5,
128.8, 137.8, 141.1, 166.6, 179.6, 196.1; FT-IR (neat) ν 3419,
3271, 2956, 2923, 2852, 1732, 1709, 1645, 1456, 1254, 1196,
1078, 1043, 877, 845 cm-1; HRMS (FAB) [M + H]+ calcd for
(5S,8R,9R)-2-((1S,2R)-(Z)-1,2-Epoxyhex-3-enyl)-8-(hy-
droxy-phenyl-methyl)-8-methoxy-3-methyl-9-triethylsi-
loxy-1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione (45A): 1H
NMR (400 MHz, CDCl3) δ 0.51 (6H, q, J ) 8.0 Hz), 0.91 (9H,
t, J ) 8.0 Hz), 1.05 (3H, t, J ) 7.5 Hz), 1.76 (3H, s), 2,17-2.36
(2H, m), 3.49 (3H, s), 3.73 (1H, bd, J ) 1.8 Hz), 4.06 (1H, bdd,
J ) 8.9, 1.1 Hz), 4.69 (1H, s), 5.06 (1H, bt, J ) 10.3 Hz), 5.09
(1H, s), 5.83 (1H, dt, Jd ) 10.9, Jt ) 7.5 Hz), 5.93 (1H, bs),
7.31-7.43 (5H, m); 13C NMR (150 MHz, CDCl3) δ 4.6, 5.1, 6.5,
14.1, 21.3, 52.7, 52.8, 54.6, 75.1, 75.7, 90.1, 91.8, 114.4, 123.9,
127.5, 128.4, 128.7, 138.1, 141.0, 166.8, 179.8, 196.1; FT-IR
(neat) ν 3402, 2952, 2920, 2875, 2850, 1732, 1711, 1637, 1458,
1406, 1194, 1041, 731 cm-1; HRMS (FAB) [M + H]+ calcd for
C25H34O7NSi 488.2105, found 488.2124; [R]32 -4.7 (c 0.14,
D
CHCl3).
C28H40O7NSi 530.2574, found 530.2562; [R]21 -64 (c 0.04,
D
(5S,8S,9R)-8-Benzoyl-2-((1S,2R)-(Z)-1,2-epoxyhex-3-enyl)-
8-methoxy-3-methyl-9-trimethylsilanyloxy-1-oxa-7-
azaspiro[4.4]non-2-ene-4,6-dione (48). To a CH2Cl2 solution
(0.16 mL) of methyl ether 47 (2.0 mg, 4.10 µmol) and NaHCO3
(7.1 mg, 0.0845 mmol) was added Dess-Martin periodinane
(11.1 mg, 0.0261 mmol) at 0 °C. After 5 min, the reaction
mixture was warmed to room temperature and added to a
solution of a mixture (0.1 mL, 5.64 µmol) of CH2Cl2 and H2O
(1000:1). After stirring for 30 min at that temperature, the
reaction was quenched by the addition of saturated aqueous
NaHCO3 and diluted with ethyl acetate. The organic materials
were extracted with ethyl acetate three times, and the
combined organic extracts were washed with saturated aque-
ous NaHCO3 twice, dried over anhydrous Na2SO4, and con-
centrated in vacuo after filtration. Purification by thin-layer
chromatography (ethyl acetate/hexane ) 1:2) gave 1.8 mg
(90%) of benzoyl product 48 as a colorless oil: 1H NMR (400
MHz, CDCl3) δ -0.12 (9H, s), 1.03 (3H, t, J ) 7.5 Hz), 1.80
(3H, s), 2.17-2.35 (2H, m), 3.43 (3H, s), 3.74 (1H, bd, J ) 1.6
Hz), 4.12 (1H, ddd, J ) 9.0, 1.6, 0.9 Hz), 4.52 (1H, s), 5.05
CHCl3).
(5S,8R,9R)-2-((1S,2R)-(Z)-1,2-Epoxyhex-6-enyl)-8-hy-
droxy-8-(hydroxy-phenyl-methyl)-3-methyl-9-triethylsi-
loxy-1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione (45B): 1H
NMR (400 MHz, CDCl3) δ 0.59 (6H, dq, Jd ) 3.2, Jq ) 8.0 Hz),
0.93 (9H, t, J ) 7.9 Hz), 1.05 (3H, t, J ) 7.5 Hz), 1.78 (3H, s),
2.19-2.35 (2H, m), 3.77 (1H, bd, J ) 1.7 Hz), 4.14 (1H, bdd, J
) 8.0, 1.1 Hz), 4.83 (1H, s), 5.08 (1H, bt, J ) 10.0 Hz), 5.11
(1H, s), 5.79 (1H, s), 5.86 (1H, dt, Jd ) 10.8, Jt ) 7.8 Hz), 6.12
(1H, bs), 7.33-7.52 (5H, m); 13C NMR (150 MHz, CDCl3) δ 4.7,
5.1, 6.5, 14.0, 21.3, 52.7, 55.1, 71.2, 72.6, 86.4, 94.3, 114.5,
123.6, 127.1, 128.6, 128.8, 138.1, 141.4, 164.2, 183.1, 199.1;
FT-IR (neat) ν 3346, 2958, 2877, 2854, 1732, 1697, 1625, 1456,
1412, 1379, 1194, 1068, 827, 729 cm-1; HRMS (FAB) [M + H]+
calcd for C27H38O7NSi 516.2418, found 516.2427; [R]21 -130
D
(c 0.04, CHCl3).
(5S,9S)-8-(Z)-Benzylidene-2-((2S,3R)-(Z)-3-but-1-enyl
oxiranyl)-3-methyl-9-triethylsiloxy-1-oxa-7-azaspiro[4.4]-
non-2-ene-4,6-dione (45): 1H NMR (400 MHz, CDCl3) δ 0.65
J. Org. Chem, Vol. 70, No. 14, 2005 5653

Hayashi et al.
(6H, quint., J ) 7.6 Hz), 0.95 (9H, t, J ) 7.9 Hz), 1.06 (3H, t,
J ) 7.5 Hz), 1.88 (1H, s), 2.18-2.37 (2H, m), 3.78 (1H, bd, J )
1.9 Hz), 4.15 (1H, bdd, J ) 9.0, 1.2 Hz), 5.09 (1H, bdd, J )
10.7, 9.1 Hz), 5.23 (1H, bd, J ) 2.0 Hz), 5.84 (1H, bs), 5.85
(1H, bdt, Jd ) 15.0, Jt ) 7.5 Hz), 7.20-7.37 (5H, m), 7.72 (1H,
bs); 13C NMR (150 MHz, CDCl3) δ 4.7, 5.1, 6.6, 14.1, 21.3, 52.7,
54.8, 74.6, 92.0, 104.0, 114.5, 123.7, 127.0, 127.7, 129.0, 134.1,
135.0, 141.3, 164.7, 180.5, 195.2; FT-IR (neat) ν 3276, 2958,
2935, 2877, 1743, 1712, 1697, 1641, 1452, 1408, 1184,
1137, 1068, 827, 746 cm-1; HRMS (FAB) [M + H]+ calcd for
(3S,4S)-5-(Z)-Benzylidene-4-hydroxy-3-methoxy-3-pro-
pionyl-pyrrolidin-2-one (51′). To a THF solution (0.3 mL)
of the methyl ether 51 (2.5 mg, 0.0580 mmol) was added a
THF solution of TBAF (1 M, 0.015 mL, 0.015 mmol) at -20
°C. After stirring for 20 h at that temperature, the reaction
mixture was quenched by the addition of pH 7.0 phosphate
buffer, and the organic materials were extracted with chloro-
form three times, dried over anhydrous Na2SO4, and concen-
trated in vacuo after filtration. Purification by thin-layer
chromatography (ethyl acetate/hexane ) 1:2) gave 0.8 mg
(50%) of alcohol 51′ as a colorless oil along with the recovery
of 51 (1.0 mg, 40%). Enantiomeric excess of 51′ was determined
as >99.5% by chiral HPLC analysis [HPLC conditions: Chiral-
pak AD-H column, 2-propanol/hexane ) 1:20, 1.0 mL/min,
retention times, 21.09 min (major), 23.85 min (minor)]: 1H
NMR (400 MHz, CDCl3) δ 1.04 (3H, t, J ) 7.1 Hz), 2.69-2.95
(2H, m), 3.32 (1H, bd, J ) 1.4 Hz), 3.55 (3H, s), 5.04 (1H, bdd,
J ) 9.1, 1.0 Hz), 5.92 (1H, s), 7.17-7.38 (5H, m), 7.72 (1H,
bs); 13C NMR (150 MHz, CDCl3) δ 6.7, 32.5, 54.1, 69.7, 90.6,
103.1, 127.1, 127.4, 129.1, 134.8, 136.1, 167.3, 210.2; FT-IR
(neat) ν 3338, 2924, 2852, 1734, 1716, 1689, 1452, 1180, 1118,
758 cm-1; HRMS (FAB) [M + H]+ calcd for C15H18O4N
276.1236, found 276.1227.
C27H36O5NSi 482.2363, found 482.2388; [R]32 +146 (c 0.17,
D
CHCl3).
(3S,4S)-5-(Z)-Benzylidene-3-methoxy-3-propionyl-4-tri-
isopropylsiloxy-pyrrolidin-2-one (51). To a solution of
ketone 7 (9.0 mg, 0.0217 mmol) and Ag2O (251 mg, 1.09 mmol)
in CH3CN (0.7 mL) was added iodomethane (0.12 mL, 2.17
mmol), and the mixture was stirred at 0 °C for 5 h in the dark.
The reaction mixture was filtered through a pad of Celite and
washed AcOEt. The filtrate was concentrated in vacuo, and
the residue was purified by preparative thin-layer chroma-
tography (diethyl ether:chloroform ) 1:7) and afforded methyl
ether 51 (2.9 mg, 31%) as a colorless oil along with the recovery
1
of the ketone 7 (2.7 mg, 30%): H NMR (400 MHz, CDCl3) δ
1.02 (3H, t, J ) 7.2 Hz), 1.09-1.19 (21H, m), 2.54 (1H, dq, Jd
) 19.1, Jq ) 7.1 Hz), 2.69 (1H, dq, Jd ) 19.1, Jq ) 7.2 Hz),
3.59 (3H, s), 5.16 (1H, bd, J ) 1.6 Hz), 5.84 (1H, s), 7.19-7.25
(3H, m), 7.36 (2H, t, J ) 7.7 Hz), 7.75 (1H, bs); 13C NMR (150
MHz, CDCl3) δ 6.7, 12.6, 17.8, 17.9, 33.2, 54.0, 75.3, 91.9, 103.8,
127.0, 127.5, 129.1, 135.0, 136.0, 169.2, 203.5; FT-IR (neat) ν
3230, 2945, 2868, 1738, 1722, 1684, 1464, 1186, 1138, 883, 808,
679 cm-1; HRMS (FAB) [M + H]+ calcd for C24H38O4NSi
(3S,4R)-1-(5-(Z)-4-Hydroxy-2,3-dimethoxy-4,5-dihydro-
3H-pyrrol-3-yl)-propan-1-one (52′). To a THF solution (0.2
mL) of the dimethoxy product 52 (3.9 mg, 0.0875 mmol) was
added a THF solution of TBAF (1.0 M, 0.02 mL, 0.02 mmol)
at -20 °C. After stirring for 20 h at that temperature, the
reaction mixture was quenched by the addition of pH 7.0
phosphate buffer, and the organic materials were extracted
with chloroform three times, dried over anhydrous Na2SO4,
and concentrated in vacuo after filtration. Purification by thin-
layer chromatography (ethyl acetate/hexane ) 1:3) gave 2.4
mg (96%) of a two diastereomer mixture of 52′ as a colorless
oil. Enantiomeric excess of 52′ was determined as 0.3% by
chiral HPLC analysis [HPLC conditions: Chiralpak AD-H
column, 2-propanol/hexane ) 1:40, 1.0 mL/min, retention times
10.51, 8.12, and 21.88 min, 28.33 min]: FT-IR (neat) ν 3475,
2925, 2852, 1716, 1606, 1595, 1441, 1338, 1076, 1012, 694
432.2570, found 432.2582; [R]25 +117 (c 0.19, CHCl3).
D
(3S,4R)-1-(5-(Z)-Benzylidene-2,3-dimethoxy-4-triiso-
propylsiloxy-4,5-dihydro-3H-pyrrol-3-yl)-propan-1-one
(52). To a solution of ketone 7 (9.8 mg, 0.0236 mmol) and Ag2O
(270 mg, 1.17 mmol) in CH3CN (0.5 mL) was added iodo-
methane (0.14 mL, 2.36 mmol), and the mixture was stirred
at room temperature for 10 h in the dark. The reaction mixture
was filtered through a pad of Celite and washed withAcOEt.
The filtrate was concentrated in vacuo, and the residue was
purified by preparative thin-layer chromatography (AcOEt/
hexane ) 1:5) and afforded dimethoxy product 52 (5.6 mg,
53%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.97 (3H,
t, J ) 7.1 Hz), 1.04-1.18 (2H, m), 2.30 (1H, dq, Jd ) 18.7, Jq
) 7.0 Hz), 2.57 (1H, dq, Jd ) 18.7, Jq ) 7.2 Hz), 3.47 (3H, s),
4.05 (3H, s), 5.27 (1H, bd, J ) 1.5 Hz), 6.00 (1H, bd, J ) 1.2
Hz), 7.18 (1H, t, J ) 7.3 Hz), 7.32 (2H, t, J ) 7.6 Hz), 7.81
(2H, d, J ) 7.7 Hz); 13C NMR (100 MHz, CDCl3) δ 6.9, 12.7,
17.8, 17.9, 32.8, 54.0, 56.2, 81.0, 94.0, 113.5, 126.5, 128.2, 129.0,
136.4, 147.9, 172.8, 202.1; FT-IR (neat) ν 2942, 2927, 2868,
cm-1
.
Acknowledgment. We thank Dr. Osamu Ando at
Sankyo Co., Ltd., for a sample of synerazol. This work
was partially supported by a Grand-in-Aid for Scientific
Research on Priority Areas (A) “Creation of Biologically
Functional Molecules” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Copies of 1H and 13
C
NMR and IR of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1732, 1653, 1604, 1595, 1464, 1327, 1122, 883, 818, 692 cm-1
;
HRMS (FAB) [M + H]+ calcd for C25H40O4NSi 446.2727, found
446.2743; [R]29 +183 (c 0.25, CHCl3).
JO050664X
D
5654 J. Org. Chem., Vol. 70, No. 14, 2005