Stereoselective total synthesis of (+)-scyphostatin via a π-facially selective Diels-Alder reaction

Article abstract of DOI:10.1021/jo070337k

(Chemical Equation Presented) A stereoselective total synthesis of scyphostatin is described. The hydrophilic moiety was stereoselectively synthesized via (i) a highly π-facially selective Diels-Alder reaction of a spirolactone generated from L-tyrosine a

Full text of DOI:10.1021/jo070337k

Stereoselective Total Synthesis of (+)-Scyphostatin via a π-Facially
Selective Diels-Alder Reaction
Ryukichi Takagi,* Wataru Miyanaga, Kengo Tojo, Shinjiro Tsuyumine, and Katsuo Ohkata
Department of Chemistry, Graduate School of Science, Hiroshima UniVersity, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan
rtakagi@hiroshima-u.ac.jp
ReceiVed February 19, 2007
A stereoselective total synthesis of scyphostatin is described. The hydrophilic moiety was stereoselectively
synthesized via (i) a highly π-facially selective Diels-Alder reaction of a spirolactone generated from
L-tyrosine and (ii) a hydroxy group directed epoxidation as key reactions. The hydrophilic moiety was
combined with the hydrophobic side chain in the final stage. Total synthesis was achieved by overcoming
the instability of the C5-C6 epoxide ring with carefully executed mild reactions. In the course of this
work, it was revealed that we had mistakenly assigned the relative stereochemistry of the C5-C6 epoxide
ring of the end product in our previous model study. Revision of the stereochemical assignment in the
model study is described. A diastereomer of (+)-scyphostatin epimeric at C5 and C6 (the epoxide region)
was also synthesized.
Introduction
reported synthetic efforts,4 and various analogues5 of scyphos-
tatin 1 have been synthesized. Thus far, the total synthesis of
scyphostatin 1 has been reported only by Katoh et al.6 The
difficulty lies in the extremely labile nature of the compound,
especially in a condensed state, and its highly functionalized
Scyphostatin 1, which was isolated from the mycelial extract
of Dasyscyphus mollissima by Ogita et al. (Sankyo Co., Ltd.,
Japan) in 1997, was the first discovered potent small molecule
inhibitor of neutral sphingomyelinase (N-SMase) (Scheme 1).1
Scyphostatin 1 consists of a hydrophobic side chain 2 and a
hydrophilic 4,5-epoxy-2-cyclohexen-1-one 3. Our interest in
such amphiphilic natural products has inspired us to carry out
synthetic studies on scyphostatin 1.2,3 Other groups have also
(3) Our synthetic studies on the hydrophilic moiety of scyphostatin 1:
(a) Takagi, R.; Miyanaga, W.; Tamura, Y.; Ohkata, K. Chem. Commun.
2002, 2096. (b) Miyanaga, W.; Takagi, R.; Ohkata, K. Heterocycles 2004,
64, 129. (c) Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem.
2005, 3, 2031. Our synthetic study on the hydrophobic moiety of
scyphostatin 1: (d) Takagi, R.; Tsuyumine, S.; Nishitani, H.; Miyanaga,
W.; Ohkata, K. Aust. J. Chem. 2004, 57, 439.
(4) Synthetic studies on the hydrophilic moiety of scyphostatin 1: (a)
Gurjar, M. K.; Hotha, S. Heterocycles 2000, 53, 1885. (b) Katoh, T.; Izuhara,
T. Tetrahedron Lett. 2000, 41, 7651. (c) Izuhara, T.; Katoh, T. Org. Lett.
2001, 3, 1653. (d) Runcie, K. A.; Taylor, R. J. K. Org. Lett. 2001, 3, 3237.
(e) Fujioka, H.; Kotoku, N.; Sawama, Y.; Nagatomi, Y.; Kita, Y.
Tetrahedron Lett. 2002, 43, 4825. (f) Izuhara, T.; Yokota, W.; Inoue, M.;
Katoh, T. Heterocycles 2002, 56, 553. (g) Murray, L. M.; O’Brien, P.;
Taylor, R. J. K. Org. Lett. 2003, 5, 1943. (h) Pitsinos, E. N.; Cruz, A. Org.
Lett. 2005, 7, 2245. (i) Katoh, T.; Izuhara, T.; Yokota, W.; Inoue, M.;
Watanabe, K.; Nobeyama, A.; Suzuki, T. Tetrahedron 2006, 62, 1590. (j)
Stevenson, N. G.; Savi, C. D.; Harrity, J. P. A. Synlett 2006, 2272. (k)
Pitsinos, E. N.; Moutsos, V. I.; Vageli, O. Tetrahedron Lett. 2007, 48, 1523.
Synthetic studies on the hydrophobic moiety of scyphostatin 1: (l) Hoye,
T. R.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481. (m) Tan, Z.; Negishi,
E.-i. Angew. Chem., Int. Ed. 2004, 43, 2911. (n) McAllister, G. D.; Taylor,
R. J. K. Tetrahedron Lett. 2004, 45, 2551.
* To whom correspondence should be addressed. Tel.: +81-82-424-7434.
Fax: +81-82-424-0727.
(1) (a) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita, T.
J. Am. Chem. Soc. 1997, 119, 7871. (b) Nara, F.; Tanaka, M.; Hosoya, T.;
Suzuki-Konagai, K.; Ogita, T. J. Antibiot. 1999, 52, 525. (c) Nara. F.;
Tanaka, M.; Masuda-Inoue, S.; Yamamoto, Y.; Doi-Yoshioka, H.; Suzuki-
Konagai, K.; Kumakura, S.; Ogita, T. J. Antibiot. 1999, 52, 531. (d) Saito,
S.; Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2002, 2, 505.
(2) (a) Takagi, R.; Sasaoka, A.; Kojima, S.; Ohkata, K. Chem. Commun.
1997, 1887. (b) Takagi, R.; Sasaoka, A.; Nishitani, H.; Kojima, S.; Hiraga,
Y.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 925. (c) Nishitani, H.;
Sasaoka, A.; Tokumasu, M.; Ohkata, K. Heterocycles 1999, 50, 35. (d)
Tokumasu, M.; Ando, H.; Hiraga, Y.; Kojima, S.; Ohkata, K. J. Chem.
Soc., Perkin Trans. 1 1999, 489. (e) Hiraga, Y.; Ago, M.; Tokumasu, M.;
Kaku, K.; Ohkata, K. Aust. J. Chem. 2000, 53, 909. (f) Ohmori, N. Chem.
Commun. 2001, 1552. (g) Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002,
755.
10.1021/jo070337k CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/04/2007
J. Org. Chem. 2007, 72, 4117-4125
4117

Takagi et al.
SCHEME 1. Synthetic Plane of Scyphostatin
SCHEME 2 π-Facially Selective Diels-Alder Reaction of 7
SCHEME 3. Synthesis of 15 from 9a
profile.1b Our synthetic plan for scyphostatin 1 was to synthesize
the hydrophobic carboxylic acid 2 and the hydrophilic cyclo-
hexenone 3 moieties separately and to combine them in a late
stage of the total synthesis. The stereoselective synthesis of the
hydrophobic carboxylic acid 2 was achieved by the attachment
of the three components of vinyl iodide 4, organozinc compound
5, and phosphonate 6.3d In this paper, the stereoselective total
synthesis of scyphostatin 1 and revision of the stereochemical
assignment in our previous model study are described.
Results and Discussion
L-Tyrosine was selected as the starting material because of
the presence of the 6-membered ring and the requisite stereo-
center in the appropriate position, and the synthetic route
depicted in Scheme 1 was envisioned. On the basis of our model
studies,3a-c we decided to proceed with the key spirolactone
7,7 readily prepared from L-tyrosine. The Diels-Alder reaction
of spirolactone 7 with cyclopentadiene proceeded with high
π-facial selectivity to give a mixture of endo adducts 8a and
8b (8a:8b ) 1:1, 98%), resulting from reaction to the face
bearing the spiro ring oxygen atom (Scheme 2).8 Treatment of
the mixture of 8a and 8b with LiOH/H2O2, followed by 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) gave a mix-
ture of only two of the possible epoxides, which were found to
be readily separable.9 Since it was easier to separate 9, 8 was
used routinely as a diastereomeric mixture. Interestingly, the
products turned out to result from opposite facial selectivity,
i.e., exo-epoxide 9a and endo-epoxide 9b (48%, two steps). The
absolute stereochemistry of 8a,b and 9a,b was determined by
1H NMR dif-NOE experiments (Figure 1).
(5) (a) Arenz, C.; Giannis, A. Angew. Chem., Int. Ed. 2000, 39, 1440.
(b) Arenz, C.; Gartner, M.; Wascholowski, V.; Giannis, A. Bioorg. Med.
Chem. 2001, 9, 2901. (c) Pitsinos, E. N.; Wascholowski, V.; Karaliota, S.;
Rigou, C.; Couladouros, E. A.; Giannis, A. Chem. Biol. Chem. 2003, 4,
1223. (d) Kenworthy, M. N.; McAllister, G. D.; Taylor, R. J. K. Tetrahedron
Lett. 2004, 45, 6661. (e) Claus, R. A.; Wu¨stholz, A.; Mu¨ller, S.; Bockmeyer,
C. L.; Riedel, N. H.; Kinscherf, R.; Deigner, H.-P. Chem. Biol. Chem. 2005,
6, 726.
Since exo-epoxide 9a met our strategic needs, the synthesis
was carried on from this compound (Scheme 3). The reductive
cleavage of the epoxide ring with SmI2,10 followed by protection
(6) Inoue, M.; Yokota, W.; Murugesh, M. G.; Izuhara, T.; Katoh, T.
Angew. Chem., Int. Ed. 2004, 43, 4207.
(7) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33, 5477.
(8) (a) Takagi, R.; Miyanaga, W.; Tamura, Y.; Kojima, S.; Ohkata, K.
Heterocycles 2003, 60, 785. (b) Ohkata, K.; Tamura, Y.; Brandon, B. S.;
Takagi, R.; Miyanaga, W.; Kojima, S.; Paquette, L. A. J. Am. Chem. Soc.
2004, 126, 16783.
(9) Both 8a and 9a were obtained as colorless oils. In contrast, both 8b
and 9b were obtained as white crystals. So, both 8b and 9b could easily be
obtained as single isomers by recrystallization of the diastereomer mixtures.
The undesired isomer 8b in this strategy can easily be recycled by converting
it back to 7 by the retro-Diels-Alder reaction.
4118 J. Org. Chem., Vol. 72, No. 11, 2007

Synthesis of (+)-Scyphostatin
SCHEME 4. Synthesis of 18 from 15
FIGURE 1. Absolute stereochemistry of the cycloaddition products
8 and 9.
was tentatively assigned to be the same as that in the natural
product on the basis of 1H NMR dif-NOE experiments carried
out for the assignment of 13, in which NOE enhancement
between H3 and H5 (2.4%) was observed (Figure 3).
The attempt to complete the total synthesis is described in
Scheme 4. The removal of the Cbz protecting group by
hydrogenolysis was not straightforward and required the use
of Pd(OH)2/C in the presence of 1 N HCl. Although several
conditions [Pd/C (100 wt %), MeOH, 72 h; PtO2 (25 wt %),
MeOH/AcOH (1/1), 4 days] were attempted, both the long
reaction time and the large amount of the catalyst were
necessary, and the C1-silyl protecting group was cleaved off
under the reaction conditions. The hydrophilic moiety 15 was
combined with the hydrophobic carboxylic acid 2 using the
optimized Cbz removal conditions and subsequent amidation
(64%, two steps). Swern oxidation of 16 furnished 17 with
spontaneous extrusion of the TsO group (71%).12 Removal of
the TBDPS group with tris(dimethylamino)sulfonium difluo-
rotrimethylsilicate (TASF)13 in pyridine afforded 18 in satisfac-
tory yield (70%).14 Disappointingly, however, the spectroscopic
data [1H and 13C NMR] of 18 were not identical to those of
natural scyphostatin.
FIGURE 2. Absolute stereochemistry of 12.
FIGURE 3. NOE experiments on 13 and the proposed structure
of 15.
In order to reveal the reason for the spectral difference
between 18 and the natural product, we decided to re-examine
the stereochemical assignment in our previous model study
(Scheme 5). Bromohydrin 23, obtained from epoxide 19 in the
model study,3c was converted to 24, an analogue of the
hydrophilic moiety. Since the relative stereochemistry of 19 had
been confirmed by X-ray structural analysis,3b the relative
of secondary hydroxyl group with triethylsilyl (TES) group
afforded 10 (83%, two steps). The retro-Diels-Alder product
11 was obtained by heating (230 °C) 10 in the presence of
maleic anhydride (100%). Reduction of 11 with NaBH4/CeCl3
1
gave 12 as a single isomer (95%). H NMR dif-NOE experi-
ments indicated that alcohol 12 was a product of axial attack
of the hydride (Figure 2). The epoxidation of alcohol 12 with
mCPBA gave epoxide 13 as a single isomer (99%). Tosylate
14 was obtained by tosylation of epoxide 13 (90%). The lactone
ring of 14 was easily reduced with NaBH4,11 and the following
removal of the TES group (C9) with tetrabutylammonium
fluoride (TBAF) and reprotection of the C1-hydroxy group with
a tert-butyldiphenylsilyl (TBDPS) group gave 15 (94%). The
TBDPS protection of the C1-hydroxy group was necessary for
the ensuing hydrogenolysis of the benzyloxycarbonyl (Cbz)
group. The stereochemistry of the C5-C6 epoxide ring of 15
1
stereochemistry of 24 was assured. The H NMR spectrum of
24 turned out to be identical to that of 22,3a,b the end product in
refs 3a,b. Thus, the relative stereochemistry of 22 was the same
as that of 24, and the original stereochemical assignment of
epoxide 213a,b based upon NOE experiments was incorrect. This
(12) Other methods of oxidations (e.g., IBX; Dess-Martin periodinane;
TPAP, NMO) of 15 were also attempted. However, the epoxy-cyclohex-
enone compound was not obtained.
(13) (a) Noyori, R.; Nishida, I.; Sakata, J.; Mishisawa, M. J. Am. Chem.
Soc. 1980, 102, 1223. (b) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler,
S. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(14) When 17 was treated with TBAF in the presence of AcOH (10 equiv)
at 0 °C for 3 h, 18 was obtained in 27% yield (conversion yield: 61%)
along with recovered 17 (66% recovered).
(10) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 2596.
(11) Wipf, P.; Kim, Y. J. Org. Chem. 1993, 58, 1649.
J. Org. Chem, Vol. 72, No. 11, 2007 4119

Takagi et al.
SCHEME 5. Revision of the Stereochemical Assignment of 22
SCHEME 6. Synthesis of 26a,b
As for determination of the absolute stereochemistry in the
series involving 13, we could not resort to X-ray structural
analysis due to lack of appropriate single crystals. Therefore,
we decided to determine the absolute stereochemistry by
1
comparing the H NMR dif-NOE experiments among 13 and
its diastereomers (Scheme 6). To this end, 11 was epoxidized
to give 25 as a single isomer. The absolute stereochem-
istry of 25 could not be determined with certainty from NOE
experiments, since signal enhancement (3.6%) between H3 and
H5 was only slightly larger than that (1.9%) observed
for 21, for which we had mistakenly assigned stereo-
chemistry. The epoxide 25 was then reduced to give a mixture
of 26a and 26b, diastereomeric in regards with the relative
stereochemistry of the epoxide and the C7 hydroxy group.
Neither the spectral data of 26a nor 26b turned out to be
identical to that of 13, suggesting that we had three different
diastereomers in hand. In the NOE experiments of 26a,b, the
NOE enhancement between H3 and H5 was clearly larger than
that of 13. Also, the NOE enhancement between H6 and H7 of
13 and 26a was larger than that of 26b. This analysis implied that
13 was a product of C7-hydroxy group directed epoxidation as it
happened to be in the model system (Figure 4). It followed that
18 was a diastereomer of scyphostatin epimeric at C5 and C6.
suggested that the C7-hydroxy group had actually directed the
epoxidation reaction to occur from the same side as this group,
as is the usual case.15 A similar stereochemical revision has
been reported in the assignment of structurally related natural
product, calafianin.16
FIGURE 4. Revised structures of 13-18.
In accordance with the results from the stereochemical
reexamination, we modified our synthetic strategy. Thus, we
decided to utilize the hydroxyl group that is formed upon ring
opening of the lactone to direct epoxidation to the opposite side
of the ring (Scheme 7). On the basis of the synthetic study of
(15) In the model study (refs 3a,b), we could not obtain the diastereomer
epimeric at C5 and C6 (the epoxide region) and thus could not compare
the NOE enhancement pattern between the diastereomers. The epoxidation
of the C7-OAc protected 20 with mCPBA was also examined in order to
confirm the stereochemical assignment. Although the yield was low (5%
yield), the facial selectivity of the epoxidation was the same as that of 20.
(16) (a) Encarnacio´n, R. D.; Sandoval, E.; Malmstrøm, J.; Christophersen,
C. J. Nat. Prod. 2000, 63, 874. (b) Ogamino, T.; Obata, R.; Tomoda, H.;
Nishiyama, S. Bull. Chem. Soc. Jpn. 2006, 79, 134.
4120 J. Org. Chem., Vol. 72, No. 11, 2007

Synthesis of (+)-Scyphostatin
SCHEME 7. Synthesis of 31 from 12
SCHEME 8. Completion of (+)-Scyphostatin
of 30 gave 31 as a single isomer with diol 33. As the results
indicate, treatment of 30 at 0 °C gave the best result (Table 1,
entry 2).
18, 12 was converted to 30 as follows. The C7-hydroxy group
of 12 was protected as an acetate,17 and then the spirolactone
ring was reduced to diol 28. Removal of the C9-TES group,
followed by silylation of the C1-hydroxy group with TBDP-
SOTf, gave 30.18,19 Stereoselective epoxidation by the directing
effect of the C4-hydroxy group was thus examined (Table 1).
The stereochemistry of the C5-C6 epoxide ring was determined
by comparing the 1H NMR dif-NOE experiments between those
of 31 and 32-minor (Figure 5). Treatment of 28 with mCPBA
The end game is described in Scheme 8. Removal of the Cbz
group by hydrogenolysis was more problematic than in the
synthesis of the diastereomer 18 because of the sensitivity of
the C5-C6 epoxide ring (Table 2). The hydrogenolysis of 31
with PtO2 was unsuccessful, even in the presence of AcOH
(Table 2, entry 1). When 31 was treated with Pd(OH)2/C in the
absence of AcOH, the C5-C6 epoxide ring was cleaved by
the intramolecular nucleophilic reaction of the resulting amine
(Table 2, entry 2). This could be suppressed by the use of Pd-
(OH)2/C in the presence of AcOH (Table 2, entries 3, 4). It
was revealed that the resulting amine 31′ readily converted to
36 under the reaction conditions. Condensation of amine 31′
and the hydrophobic carboxylic acid 2 with EDCI furnished 34
(69%, two steps). Exposure of epoxide 34 to Swern oxidation
conditions furnished 35, which bears the epoxy-cyclohexenone
moiety, with the spontaneous extrusion of the AcO group (49%).
Epoxide 34 was also recovered (32%). The C5-C6 epoxide
ring seemed to have cleaved under the reaction conditions, and
the diluted conditions (0.015 M) were necessary for satisfactory
yields.20 Finally, the treatment of 35 with TBAF in the presence
of AcOH gave scyphostatin 1 in 61% yield. Spectroscopic data
[1H and 13C NMR, HRMS] of synthetic scyphostatin 1 were
identical to those of natural scyphostatin.1 There was also good
agreement obtained in the optical rotation value between those
of synthetic and natural scyphostatin.
FIGURE 5. Absolute stereochemistry of 31 and 32-minor.
afforded a mixture of diastereomers 32 (major:minor ) 21:1,
Table 1, entry 1). Compared to the C5-C6 epoxide ring of 13-
15, that of 32 was sensitive to acidic conditions (epoxidation
with mCPBA; silylation of the C1-hydroxy group with TBDP-
SOTf; removal of the C9-TES group with AcOH and H2O; in
CDCl3). The formation of the minor isomer was reasoned
to be due to the presence of the free primary hydroxyl
group. Thus, in order to improve the stereochemistry and the
yield of epoxidation with mCPBA, the epoxidation of 30, in
which the primary hydroxyl group is protected with a silyl
group, was examined (Table 1, entries 2-6). The epoxidation
In summary, the stereoselective total synthesis of (+)-
scyphostatin was achieved from L-tyrosine. The high π-facially
selective Diels-Alder reaction of spirolactone 7 and a stereo-
selective epoxidation directed by the C4 hydroxy group were
keys to the success. This synthetic study suggested that the high
reactivity of the C5-C6 epoxide ring may be the cause of the
extremely labile nature of scyphostatin.21 Also, in the course
of this work, it was revealed that we had mistakenly assigned
the relative stereochemistry of the C5-C6 epoxide ring of the
(17) Similar to the synthesis of the diastereomer 18, the tosylation of 12
was also attempted. However, after generation of the tosylate, a subsequent
spontaneous reaction with the chloride ion occurred under the reaction
conditions.
(18) Kobayashi, S.; Takahashi, Y.; Komano, K.; Alizadeh, B. H.;
Kawada, Y.; Oishi, T.; Tanaka, S.; Ogasawara, Y.; Sasaki, S.; Hirama, M.
Tetrahedron 2004, 60, 8375.
(19) TBDPS protection of the C1-hydroxy group of 29 was more difficult
than the synthesis of 15, and a more reactive reagent, TBDPSOTf, was
necessary.
(20) When a reaction mixture of 0.023 M was used for the Swern
oxidation, 35 (36% yield, conversion yield: 49%) and the recovered 34
(26% recovered) were obtained.
(21) The sensitivity of the cyclohexenone moiety to basic conditions has
been mentioned by Katoh et al (ref 6).
J. Org. Chem, Vol. 72, No. 11, 2007 4121

Takagi et al.
TABLE 1. Stereoselective Epoxidation of 28 and 30 by the Directing Effect of the C4-Hydroxy Group
TABLE 2. Hydrogenolysis of 31
The solvent was removed in vacuo. The residue was purified by
column chromatography (silica gel, EtOAc/hexane 1:1) to give a
mixture of 8a and 8b (94.8 mg, 98%, 8a:8b ) 1:1). The mixture
of 8a and 8b was separated by preparative TLC (SiO2, EtOAc/
hexane 1:1, multiple developments). 8a: colorless oil; [R]D27
)
+4.2 (c 1.69, CHCl3); IR (thin film) 2956, 1675, 1790, 1718, 1529,
1261, 1190 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.30 (d, J ) 7.9
Hz, 1 H), 1.45 (d, J ) 7.9 Hz, 1 H), 2.43 (t, J ) 11.9 Hz, 1 H),
2.76 (dd, J ) 10.1, 11.9 Hz, 1 H), 2.89 (bs, 1 H), 3.04 (dd, J )
3.4, 5.0 Hz, 1 H), 3.38 (bs, 2 H), 4.51 (dd, J ) 10.1, 11.9 Hz, 1
H), 5.10 (d, J ) 12.0 Hz, 1 H), 5.13 (d, J ) 12.0 Hz, 1 H), 5.72
(d, J ) 6.3 Hz, 1 H), 5.84 (dd, J ) 2.1, 5.0 Hz, 1 H), 5.88 (d, J )
10.0 Hz, 1 H), 6.11 (bs, 1 H), 6.46 (d, J ) 10.0 Hz, 1 H), 7.31-
7.40 (m, 5 H); 13C NMR (125 MHz, CDCl3) δ 47.2, 47.4, 47.5,
47.9, 48.6, 50.6, 51.0, 67.4, 81.3, 128.2 (×2), 128.4, 128.6, (×2)
131.4, 134.6, 135.3, 135.7, 147.4, 155.9, 173.6, 198.9. EI-HRMS
m/z: calcd for C22H21NO5 [M+], 379.1420; found, 379.1417. 8b:
white crystal; mp 179-181 °C (hexane/i-PrOH); [R]2D7 +14.1 (c
0.507, CHCl3); IR (thin film) 2994, 1765, 1716, 1666, 1520, 1430,
1250, 1200 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.34 (d, J ) 8.4
Hz, 1 H), 1.49 (d, J ) 8.4 Hz, 1 H), 2.12 (t, J ) 12.1 Hz, 1 H),
2.73 (dd, J ) 7.3, 12.1 Hz, 1 H), 2.94 (d, J ) 8.5 Hz, 1 H), 3.05
(dd, J ) 4.0, 8.5 Hz, 1 H), 3.12 (bs, 1 H), 3.41 (bs, 1 H), 4.65-
4.74 (m, 1 H), 5.13 (s, 2 H), 5.27 (b, J ) 4.9 Hz, 1 H), 5.85-5.90
(m, 2 H), 6.13 (dd, J ) 3.1, 5.8 Hz, 1 H), 6.45 (d, J ) 10.2 Hz, 1
H), 7.31-7.43 (m, 5 H); 13C NMR (125 MHz, CDCl3) δ 44.8 (×2),
47.2, 47.4, 48.7, 49.7, 50.8, 67.6, 80.7, 128.3 (×2), 128.4, 128.6
(×2), 131.0, 135.0, 135.1, 135.4, 147.8, 155.9, 173.5, 198.7. EI-
HRMS m/z: calcd for C22H21NO5 [M+], 379.1420; found, 379.1442.
Anal. Calcd for C22H21NO5: C, 69.64; H, 5.58. N, 3.69. Found:
C, 69.59; H, 5.53; N, 3.43.
entry
catalyst
conditions
product
1
2
3
4
PtO2 (9 wt %)
Pd(OH)2/C (21 wt %) 5 h
AcOH (3.0 equiv) 5 h
no reaction
36 (85%)
Pd(OH)2/C (19 wt %) AcOH (3.0 equiv) 5 h
31′:36 ) 1:1a
Pd(OH)2/C (17 wt %) AcOH (3.0 equiv) 30 min 31′a
a Compound 31′ was used for the next reaction without further
purification.
end product in our previous model study.3a,b Our strategy allows
for the synthesis of various analogues of scyphostatin, as evident
from the synthesis of a diastereomer of (+)-scyphostatin
epimeric at C5 and C6 (the epoxide region).
(4S)-4-Benzyloxycarbonylamino-6′,7′-epoxy-1′,3,4,4′,4′a,6′,7′,8′a-
octahydro-spiro[furan2(5H),5′(8′H)-1′,4′-methanonaphtalene]-
5′,8-dione (9). To a solution of a diastereomer mixture of 8a and
8b (2.91 g, 7.67 mmol, 1:1) in THF (38 mL) was added a solution
of 30% H2O2 (4.41 g, 38.9 mmol) and 0.5 M LiOH (8 mL, 4.0
mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 6 h
and quenched with saturated NaHSO3 and saturated NH4Cl. The
aqueous layer was extracted with EtOAc. The combined organic
Experimental Section
(4S)-4-Benzyloxycarbonylamino-1′,3,4,4′,4′a,8′a-hexahydro-
spiro[furan-2(5H),5′(8′H)-1′,4′-methanonaphthalene]-5,8′-di-
one (8). Cyclopentadiene (171 mg, 2.59 mmol), which was prepared
by thermolysis of dicyclopentadiene, was added to a solution of 77
(79.8 mg, 0.26 mmol) in CH2Cl2 (0.5 mL) at room temperature.
The reaction mixture was stirred at room temperature for 72 h.
4122 J. Org. Chem., Vol. 72, No. 11, 2007

Synthesis of (+)-Scyphostatin
layer was washed with H2O and brine, dried over Na2SO4, and
evaporated. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI)
(1.46 g, 7.60 mmol) was added to a solution of the resulting residue
in CH2Cl2 (76 mL) at room temperature. The reaction mixture was
stirred for 18 h, quenched with saturated NH4Cl, and extracted with
CH2Cl2. The combined organic layer was washed with H2O and
brine, dried over Na2SO4, and evaporated. The crude product was
purified by column chromatography (silica gel, CHCl3/MeOH, 50/
1) to give 9a and 9b as pure products (9a:9b ) 1:1, combined
yield 1.47 g, 48%). 9a: colorless oil; [R]2D7 ) +28.2 (c 1.17,
CHCl3); IR: (thin film) 2973, 1789, 1716, 1538, 1538, 1454, 1338,
1261, 1199 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.25 (d, J ) 7.7
Hz, 1 H), 1.47 (d, J ) 7.7 Hz, 1 H), 2.59 (t, J ) 12.9 Hz, 1 H),
2.84 (dd, J ) 3.1, 10.8 Hz, 1 H), 3.05 (dd, J ) 9.4, 12.9 Hz, 1 H),
3.11 (bs, 1 H), 3.13 (d, J ) 10.8 Hz, 1 H), 3.15 (s, 1 H), 3.33-
3.39 (m, 2 H), 4.44-4.52 (m, 1 H), 5.15 (bs, 2 H), 5.55 (d, J )
6.4 Hz, 1 H), 6.06 (bs, 1 H), 6.13 (bs, 1 H), 7.42-7.31 (m, 5 H);
13C NMR (125 MHz, CDCl3) δ 38.2, 42.9, 43.8, 48.5, 48.7, 50.0
(×2), 55.2, 58.8, 67.5, 81.7, 128.2 (×2), 128.4, 128.6 (×2), 133.7,
135.7, 135.9, 155.8, 172.3, 204.9. EI-HRMS m/z: calcd for C22H21-
NO6 [M+], 395.1369; found 395.1360. Anal. Calcd for C22H21-
NO6: C, 66.83; H, 5.35, N; 3.54. Found: C, 66.71; H, 5.55; N,
3.48. 9b: white solid; mp 177-179 °C (hexane/i-PrOH); [R]D27
+5.16 (c 0.53, CH3CN); IR (thin film) 2969, 2877, 1786, 1716,
1523, 1261, 1203 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.29 (d, J
) 8.2 Hz, 1 H), 1.50 (d, J ) 8.2 Hz, 1 H), 2.72 (t, J ) 12.9 Hz,
1 H), 2.86-3.02 (m, 3 H), 3.12-3.20 (m, 2 H), 3.36 (d, J ) 2.9
Hz, 1 H), 3.57 (d, J ) 2.9 Hz, 1 H), 4.48-4.56 (m, 1 H), 5.12 (s,
2 H), 5.50 (d, J ) 4.9 Hz, 1 H), 5.85 (dd, J ) 3.2, 5.5 Hz, 1 H),
6.17 (dd, J ) 2.4, 5.5 Hz, 1 H), 7.30-7.43 (m, 5 H); 13C NMR
(125 MHz, CDCl3) δ 41.0, 42.3, 44.3, 49.3 (×2), 49.8, 51.2, 54.9,
61.6, 67.7, 82.4, 128.2 (×2), 128.5, 128.6 (×2), 134.3, 135.2, 135.6,
155.8, 172.8, 204.9. EI-HRMS m/z: calcd for C22H21NO6 [M+],
395.1369; found, 395.1385. Anal. Calcd for C22H21NO6: C, 66.83;
H, 5.35; N, 3.54. Found: C, 66.87; H, 5.34; N, 3.54.
(1S,4R,4′S,4aS,5S,6S,8aR)-4′-Benzyloxycarbonylamino-6-tri-
ethylsilyloxy-1,3′,4′,4,4a,6,7,8a-octahydro-spiro[furan-2′(5H),5-
(8H)-1,4-methanonapthalene]-5′,8-dione (10). CH2I2 (305 mg,
1.14 mmol) was added to a solution of samarium metal (174 mg,
1.16 mmol) in THF (10 mL). The mixture was stirred at room
temperature for 5 h. The resulting deep blue solution was cooled
to -78 °C. The solution of SmI2 was added dropwise to a solution
of 9a (89.1 mg, 0.23 mmol) and MeOH (0.09 mL, 2.0 mmol) in
THF (1.0 mL) at -78 °C over 10 min. The reaction mixture was
stirred at -78 °C for 1 h. After it was diluted with saturated NH4-
Cl, the mixture was extracted with EtOAc. The organic layer was
washed with brine and dried over Na2SO4. The solvent was removed
in vacuo. The residue was purified by column chromatography
(silica gel, CH2Cl2/MeOH 30:1) to give the alcohol (73.8 mg, 83%)
as a white crystal: mp 165-167 °C (hexane/CHCl3); [R]27 -1.73
(c 0.525, CHCl3); IR (thin film) 3325, 2965, 1774, 171D6, 1701,
1523, 1253, 1218 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.34 (d, J
) 8.2 Hz, 1 H), 1.48 (d, J ) 8.2 Hz, 1 H), 2.19 (t, J ) 11.9 Hz,
1 H), 2.35 (dd, J ) 6.6, 18.8 Hz, 1 H), 2.47 (dd, J ) 4.8, 18.8 Hz,
1 H), 2.90 (dd, J ) 2.3, 9.6 Hz, 1 H), 2.95-3.04 (m, 2 H), 3.26
(bs, 1 H), 3.31 (bs, 1H), 3.58 (bs, 1 H), 4.00 (m, 1 H), 4.50 (td, J
) 6.3, 11.9 Hz, 1 H), 5.10 (d, J ) 12.8 Hz, 1 H), 5.12 (d, J ) 12.8
Hz, 1H), 5.73 (d, J ) 6.3 Hz, 1 H), 6.08 (bs, 1 H), 6.18 (m, 1 H),
7.30-7.38 (m, 5 H); 13C NMR (125 MHz, CDCl3) δ 37.0, 44.6,
45.2, 47.1, 48.6, 50.1, 51.4, 51.7, 67.4, 68.2, 85.8, 128.1 (×2),
128.4, 128.6 (×2), 135.1, 135.7, 136.4, 156.0, 174.8, 210.9. EI-
HRMS m/z: calcd for C22H23NO6 [M+], 397.1525; found, 397.1537.
Anal. Calcd for C22H23NO6: C, 66.49; H, 5.83; N, 3.52. Found:
C, 66.34; H, 5.92; N, 3.76.
was diluted with H2O, the mixture was extracted with CH2Cl2. The
organic layer was washed with brine and dried over Na2SO4. The
solvent was removed in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc 2:1) to give 10 (1.24 g,
100%) as a colorless oil: [R]2D7 -11.6 (c 1.12 CHCl3); IR (thin
film) 2954, 2877, 1786, 1709, 1523, 1454, 1214, 1095, 1006 cm-1
;
1H NMR (500 MHz, CDCl3) δ 0.59 (q, J ) 7.5 Hz, 6 H), 0.94 (t,
J ) 7.5 Hz, 9 H), 1.36 (d, J ) 8.2 Hz, 1 H), 1.50 (d, J ) 8.2 Hz,
1 H), 2.17 (t, J ) 11.4 Hz, 1 H), 2.32 (dd, J ) 7.6, 18.8 Hz, 1 H),
2.44 (dd, J ) 4.3, 18.8 Hz, 1 H), 2.86 (d, J ) 8.8 Hz, 1 H), 2.96
(d, J ) 8.8 Hz, 1 H), 3.01 (t, J ) 11.4 Hz, 1 H), 3.32 (bs, 2 H),
3.99 (m, 1 H), 4.43 (td, J ) 6.9, 11.4 Hz, 1 H), 5.12 (d, J ) 12.2
Hz, 1 H), 5.15 (d, J ) 12.2 Hz, 1 H), 5.35 (d, J ) 6.9 Hz, 1 H),
6.11 (bs, 1 H), 6.21 (bs, 1 H), 7.30-7.40 (m, 5 H); 13C NMR (125
MHz, CDCl3) δ 4.7 (×3), 6.6 (×3), 37.6, 45.4, 45.5, 47.3, 48.9,
50.2, 51.4, 51.6, 67.2, 69.2, 85.6, 128.0 (×2), 128.2, 128.5 (×2),
135.1, 135.9, 136.5, 155.8, 173.9, 210.2. EI-HRMS m/z: calcd for
C28H37NO6Si [M+], 511.2390; found, 511.2365. Anal. Calcd for
C28H37NO6Si: C, 65.72; H, 7.29; N, 2.74. Found: C, 65.49; H,
7.30; N, 2.95.
(3S,5S,10S)-3-Benzyloxycarbonylamino-10-triethylsilyloxy-1-
oxa-spiro[4.5]dec-6-ene-2,8-dione (11). Maleic anhydride (464 mg,
4.73 mmol) was added to a mixture of 10 (1.20 g, 2.35 mmol) in
Ph2O (110 mL) at room temperature. The reaction mixture was
heated at 230 °C for 1 h. The reaction mixture was purified by
flash column chromatography (silica gel, hexane/EtOAc 10:1) to
remove Ph2O. The residue was purified by column chromatography
(silica gel, hexane/EtOAc 2:1) to give 11 (1.05 g, 100%) as a yellow
oil: [R]2D7 -4.99 (c 0.530, CDCl3); IR (thin film) 2958, 2877,
1
1790, 1716, 1693, 1523, 1454, 1261, 1218, 1164, 1103 cm-1; H
NMR (500 MHz, CDCl3) δ 0.63 (q, J ) 7.8 Hz, 6 H), 0.96 (t, J )
7.8 Hz, 9 H), 2.12 (t, J ) 11.1 Hz, 1 H), 2.55 (dd, J ) 12.2, 16.7
Hz, 1 H), 2.75 (dd, J ) 4.8, 16.7 Hz, 1 H), 3.06 (t, J ) 11.1 Hz,
1 H), 4.32 (dd, J ) 4.8, 12.2 Hz, 1 H), 4.54 (td, J ) 6.0, 11.1 Hz,
1 H), 5.10 (d, J ) 12.2 Hz, 1 H), 5.15 (d, J ) 12.2 Hz, 1 H), 5.47
(d, J ) 6.0 Hz, 1 H), 6.02 (d, J ) 10.1 Hz, 1 H), 6.92 (d, J ) 10.1
Hz, 1 H), 7.30-7.40 (m, 5 H); 13C NMR (125 MHz, CDCl3) δ 4.7
(×3), 6.6 (×3), 32.4, 43.9, 51.2, 67.3, 72.1, 84.2, 128.1 (×2), 128.3,
128.6 (×2), 129.3, 135.8, 149.3, 155.8, 174.0, 195.9. EI-HRMS
m/z: calcd for C23H31NO6Si [M+], 445.1921; found, 445.1915.
Anal. Calcd for C23H31NO6Si: C, 62.00; H, 7.01; N, 3.14. Found:
C, 61.98; H, 7.14; N, 3.00.
(3S,5S,8R10S)-3-Benzyloxycarbonylamino-8-hydroxy-10-tri-
ethylsilyloxy-1-oxa-spiro[4.5]dec-6-ene-2-one (12). NaBH4 (26.1
mg, 0.69 mmol) was added to a solution of 11 (310 mg, 0.70 mmol)
and CeCl3‚7H2O (261 mg, 0.70 mmol) in i-PrOH (3.5 mL) and
THF (3.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C
for 40 min. After it was diluted with saturated NH4Cl, the mixture
was extracted with EtOAc. The organic layer was washed with brine
and dried over Na2SO4. The solvent was removed in vacuo. The
residue was purified by column chromatography (silica gel, hexane/
EtOAc 1:1) to give 12 (295 mg, 95%) as a yellow oil: [R]D27
+0.29 (c 0.69, CHCl3); IR (thin film) 3406, 2954, 2877, 1775, 1705,
1
1527, 1454, 1272, 1230, 1114, 1041 cm-1; H NMR (500 MHz,
CDCl3) δ 0.63 (q, J ) 7.6 Hz, 6 H), 0.96 (t, J ) 7.6 Hz, 9 H), 1.66
(q, J ) 11.9 Hz, 1 H), 1.80 (d, J ) 5.3 Hz, 1 H), 1.98 (t, J ) 11.2
Hz, 1 H), 2.25-2.32 (m, 1 H), 2.97 (t, J ) 11.2 Hz, 1 H), 3.95
(dd, J ) 1.7, 11.9 Hz, 1 H), 4.36-4.43 (m, 1 H), 4.58 (td, J ) 6.3,
11.2 Hz, 1 H), 5.10 (d, J ) 12.1 Hz, 1 H), 5.15 (d, J ) 12.1 Hz,
1 H), 5.30 (d, J ) 6.3 Hz, 1 H), 5.68 (d, J ) 10.1 Hz, 1 H), 5.81
(d, J ) 11.9 Hz, 1H), 7.30-7.41 (m, 5 H); 13C NMR (125 MHz,
CDCl3) δ 4.8 (×3), 6.7 (×3), 35.7, 39.5, 51.7, 66.6, 67.2, 71.9,
85.7, 128.1 (×2), 128.3, 128.6 (×2), 130.1, 133.6, 136.0, 155.8,
174.9. EI-HRMS m/z: calcd for C23H33NO6Si [M+], 447.2077;
found, 447.2057. Anal. Calcd for C23H33NO6Si: C, 61.72; H, 7.43;
N, 3.13. Found: C, 61.85; H, 7.31; N, 3.02.
Triethylsilyl chloride (TESCl) (0.55 mL, 3.29 mmol) was added
to a solution of the alcohol (872 mg, 2.19 mmol) and imidazole
(448 mg, 6.59 mmol) in CH2Cl2 (23 mL) at room temperature. The
reaction mixture was stirred at room temperature for 14 h. After it
(3S,5S,8R10S)-8-Acetoxy-3-benzyloxycarbonylamino-10-tri-
ethylsilyloxy-1-oxaspiro[4.5]dec-6-ene-2-one (27). To a solution
J. Org. Chem, Vol. 72, No. 11, 2007 4123

Takagi et al.
of 12 (2.62 g, 5.85 mmol) in CH2Cl2 (58 mL) at 0 °C were added
pyridine (2.40 mL, 29.3 mmol), Ac2O (0.75 mL, 7.9 mmol), and
DMAP (75.3 mg, 0.62 mmol). The reaction mixture was slowly
warmed to room temperature and stirred for 24 h. After the reaction
was quenched with saturated NH4Cl, the mixture was extracted with
CH2Cl2. The organic layer was washed with H2O and brine, dried
over Na2SO4, and evaporated. The resulting residue was purified
by column chromatography (silica gel, hexane/EtOAc 4:1 to 2:1)
to give 27 (2.83 g, 99%) as a colorless oil: [R]2D7 ) +5.02 (c 2.65,
CHCl3); IR (thin film) 2958, 2877, 1789, 1735, 1523, 1457, 1373,
1230, 1118, 1037 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.63 (q, J
) 7.9 Hz, 6 H), 0.96 (t, J ) 7.9 Hz, 9 H), 1.69-1.78 (m, 1 H),
1.99 (t, J ) 11.3 Hz, 1 H), 2.07 (s, 3 H), 2.27-2.34 (m, 1 H), 2.99
(t, J ) 11.3 Hz, 1 H), 4.00 (d, J ) 11.8 Hz, 1 H), 4.57 (td, J ) 6.6,
11.3 Hz, 1 H), 5.10 (d, J ) 12.2 Hz, 1 H), 5.15 (d, J ) 12.2 Hz,
1 H), 5.26 (bs, 1 H), 5.39-5.45 (m, 1 H), 5.72 (d, J ) 10.1 Hz, 1
H), 5.78 (d, J ) 10.1 Hz, 1 H), 7.32-7.39 (m, 5 H); 13C NMR
(125 MHz, CDCl3) δ 4.7 (×3), 6.6 (×3), 21.0, 35.4, 35.6, 51.6,
67.1, 68.5, 71.6, 85.3, 128.0, 128.2, 128.5 (×2), 129.3 (×2), 131.9,
136.0, 155.8, 170.2, 174.8. EI-HRMS m/z: calcd for C25H35NO7Si
[M+], 489.2183; found, 489.2182. Anal. Calcd. for C25H35NO7Si:
C, 61.32; H, 7.20; N, 2.86. Found C, 61.60; H, 7.36; N, 2.84.
(1S,2′S,4R,6S)-4-Acetoxy-1-(2′-benzyloxycarbonylamino-3′-
hydroxy-propyl )-6-triethylsilyloxy-2-cyclohexen-1-ol (28). To a
solution of 27 (2.75 g, 5.62 mmol) in EtOH (56 mL) at 0 °C was
added NaBH4 (412 mg, 10.9 mmol). After the reaction mixture
was stirred for 5 h, additional NaBH4 (432 mg, 11.4 mmol) was
added. After the mixture was stirred for another 3 h, another amount
of NaBH4 (216 mg, 5.72 mmol) was added. After the mixture was
stirred for 1 h, the reaction was quenched with saturated NH4Cl
and the mixture extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and evaporated. The residue
was purified by column chromatography (silica gel, hexane/EtOAc
2:1) to give 28 (2.62 g, 94%) as a colorless oil: [R]2D8 ) +5.05 (c
2.70, CHCl3); IR (thin film) 3382, 2954, 2877, 1716, 1519, 1457,
1373, 1238, 1114, 1022 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.63
(q, J ) 7.9 Hz, 6 H), 0.96 (t, J ) 7.9 Hz, 9 H), 1.70 (td, J ) 12.8,
15.6 Hz, 1 H), 1.81 (dd, J ) 4.6, 15.2 Hz, 1 H), 1.99 (dd, J ) 9.1,
15.2 Hz, 1 H), 2.06 (s, 3 H), 2.22 (dddd, J ) 1.2, 4.0, 6.7, 12.8
Hz, 1 H), 2.59 (bs, 1 H), 2.88 (s, 1 H), 3.66 (dd, J ) 5.5, 11.3 Hz,
1 H), 3.70 (dd, J ) 3.4, 11.3 Hz, 1 H), 3.75 (d, J ) 4.0, 12.8 Hz,
1 H), 3.88-3.95 (m, 1 H), 5.10 (d, J ) 12.2 Hz, 1 H), 5.13 (d, J
) 12.2 Hz, 1 H), 5.40 (ddt, J ) 2.1, 6.7, 9.8 Hz, 1 H), 5.62 (d, J
) 10.4 Hz, 1 H), 5.80 (dd, J ) 2.1, 10.4 Hz, 1 H), 5.84 (bs, 1 H),
7.30-7.37 (m, 5 H); 13C NMR (125 MHz, CDCl3) δ 4.9 (×3), 6.8
(×3), 21.1, 35.5, 36.6, 50.4, 53.4, 66.9, 69.1, 74.4, 74.9, 127.4,
128.0 (×2), 128.1, 128.5 (×2), 134.1, 136.3, 157.3, 170.5.
EI-HRMS m/z: calcd for C25H39NO7Si [M+], 493.2496; found,
493.2495. Anal. Calcd. for C25H39NO7Si: C, 60.82; H, 7.96; N,
2.84. Found C, 60.66; H, 8.06; N, 2.69.
134.8, 136.2, 157.0, 170.5. EI-HRMS m/z: calcd for C19H25NO5
[M+], 379.1631; found, 379.1613. Anal. Calcd. for C19H25NO7: C,
60.15; H, 6.64; N, 3.69. Found C, 60.03; H, 6.80; N, 3.61.
(1S,2′S,4R,6S)-4-Acetoxy-1-(2′-benzyloxycarbonylamino-3′-
tert-butyldiphenylsilyloxy-propyl)-6-hydroxy-2-cyclohexen-1-
ol (30). To a solution of 29 (41.8 mg, 0.12 mmol) in CH2Cl2 (0.6
mL) at 0 °C was added 2,6-lutidine (0.14 mL, 1.2 mmol) and
TBDPSOTf (0.10 M in CH2Cl2, 2.9 mL, 0.29 mmol). After the
mixture was stirred for 0.5 h, the reaction was quenched with
saturated NH4Cl and extracted with CH2Cl2. The organic layer was
washed with H2O and brine, dried over Na2SO4, and evaporated.
The resulting residue was purified by column chromatography
(silica gel, hexane/EtOAc 2:1) to give 30 (59.4 mg, 83%) as a
colorless oil: [R]2D8 ) +11.8 (c 2.51, CHCl3); IR (thin film) 3386,
1
2931, 2857, 1716, 1508, 1427, 1373, 1238, 1110 cm-1; H NMR
(CDCl3, 500 MHz) δ 1.06 (s, 9 H), 1.74 (ddd, J ) 7.0, 10.4, 13.4
Hz, 1 H), 1.83 (dd, J ) 5.2, 15.2 Hz, 1 H), 2.02-2.07 (m, 1 H),
2.04 (s, 3 H), 2.34 (ddd, J ) 2.9, 5.4, 13.4 Hz, 1 H), 2.87 (bs, 1
H), 3.41 (bs, 1 H), 3.67 (dd, J ) 5.2, 10.4 Hz, 1 H), 3.69-3.74
(m, 1 H), 3.77-3.82 (m, 1 H), 3.90-3.96 (m, 1 H), 5.07 (d, J )
12.2 Hz, 1 H), 5.13 (d, J ) 12.2 Hz, 1 H), 5.31 (d, J ) 6.1 Hz, 1
H), 5.38 (td, J ) 2.9, 7.0 Hz, 1 H), 5.59-5.67 (m, 2 H), 7.30-
7.46 (m, 11 H), 7.61-7.66 (m, 4 H); 13C NMR (125 MHz, CDCl3)
δ 19.2, 21.1, 26.8 (×3), 32.8, 37.6, 48.9, 66.5, 66.9, 68.2, 72.5,
72.7, 126.9, 127.8 (×2), 128.0, 128.1, 128.5 (×2), 129.8, 132.9,
133.0, 135.1, 135.5 (×4), 135.6 (×4), 136.2, 156.8, 170.3. FAB+-
HRMS (NBA) m/z: calcd for C35H44NO7Si [M + H], 618.2887;
found, 618.2868. Anal. Calcd. for C35H43NO7Si: C, 68.04; H, 7.02;
N, 2.27. Found: C, 68.04; H, 7.12; N, 2.27.
(1R,2S,2′S,3S,4R,6S)-4-Acetoxy-1-(2′-benzyloxycarbonylamino-
3′-tert-butyldiphenylsilyloxy-propyl)-2,3-epoxy-6-hydroxy-2-cy-
clohexen-1-ol (31). To a solution of 30 (17.8 mg, 29.0 µmol) in
CH2Cl2 (0.3 mL) at 0 °C was added mCPBA (23.0 mg, 87.0 µmol).
After the mixture was stirred for 48 h, additional mCPBA (23.6
mg, 89.0 µmol) was added. The reaction mixture was stirred at 0
°C for 22 h. After the mixture was diluted with CH2Cl2, the reaction
was quenched with saturated Na2S2O3 and evaporated. The mixture
was extracted with CH2Cl2. The combined organic layer was washed
with H2O and brine, dried over Na2SO4, and evaporated. The
resulting residue was purified by preparative TLC (silica gel, CH2-
Cl2/MeOH 15:1) to give 31 (15.3 mg, 84%) and 33 (1.4 mg, 7%)
as a colorless oil: 31: [R]D29 ) -9.59 (c 3.26, MeOH); IR (thin
film) 3401, 2931, 2857, 1720, 1519, 1427, 1369, 1238, 1110, 1060
cm-1; 1H NMR (500 MHz, C5D5N) δ 1.12 (s, 9 H), 2.02 (s, 3 H),
2.07 (td, J ) 8.1, 12.6 Hz, 1 H), 2.51 (ddd, J ) 3.5, 8.1, 12.6 Hz,
1 H), 2.58 (dd, J ) 3.9, 14.7 Hz, 1 H), 2.77 (dd, J ) 8.9, 14.7 Hz,
1 H), 3.41 (d, J ) 3.0 Hz, 1 H), 3.80 (d, J ) 3.0 Hz, 1 H), 4.07
(dd, J ) 6.4, 9.0 Hz, 1 H), 4.24 (dd, J ) 4.4, 9.0 Hz, 1 H), 4.37
(dd, J ) 3.5, 12.6 Hz, 1 H), 4.74-4.82 (m, 1 H), 5.22 (d, J ) 12.6
Hz, 1 H), 5.29 (d, J ) 12.6 Hz, 1 H), 5.45 (t, J ) 8.1 Hz, 1 H),
7.23-7.45 (m, 11 H), 7.87 (t, J ) 7.8 Hz, 4 H), 7.96 (d, J ) 6.4
Hz, 1 H); 13C NMR (125 MHz, C5D5N) δ 19.5, 20.9, 27.0 (×3),
33.8, 34.5, 50.4, 57.0, 61.2, 66.2, 67.3, 67.7, 68.7, 73.3, 128.0,
128.1, 128.2 (×2), 128.3, 128.7 (×4), 130.1, 130.2, 134.0, 134.1,
136.0 (×4), 138.0, 157.0, 170.1. FAB+-HRMS (NBA) m/z: calcd
for C35H44NO8Si [M + H], 634.2836; found, 634.2847. Anal. Calcd.
for C35H43NO8Si: C, 66.33; H, 6.84; N, 2.21. Found: C, 66.34;
H, 6.91; N, 2.17. 33: colorless oil; 1H NMR (500 MHz, CDCl3) δ
1.07 (s, 9 H), 1.97 (dd, J ) 4.9, 15.2 Hz, 1 H), 2.05 (bs, 2 H), 2.10
(s, 3 H), 2.25 (dd, J ) 6.7, 15.2 Hz, 1 H), 2.55 (bs, 1 H), 3.70 (dd,
J ) 4.9, 10.4 Hz, 1 H), 3.72-3.74 (m, 1 H), 3.78-3.84 (m, 3 H),
3.85-3.92 (m, 1 H), 5.06 (d, J ) 12.2 Hz, 1 H), 5.12 (m, 1 H),
5.24-5.28 (m, 1 H), 5.32 (d, J ) 5.5 Hz, 1 H), 7.31-7.46 (m, 11
H), 7.61-7.67 (m, 4 H). EI-HRMS m/z: calcd for C35H45NO9Si
[M+], 651.2864; found, 651.2850.
(1S,2′S,4R,6S)-4-Acetoxy-1-(2′-benzyloxycarbonylamino-3′-
hydroxy-propyl )-6-hydroxy-2-cyclohexen-1-ol (29). To a solution
of 28 (65.3 mg, 0.13 mmol) in THF (1.3 mL) at room temperature
was added TBAF (1.0 M in THF, 0.15 mL, 0.15 mmol). After the
mixture was stirred for 10 min, the reaction was quenched with
saturated NH4Cl and the mixture extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and evaporated.
The residue was purified by column chromatography (silica gel,
CH2Cl2/MeOH 15:1) to give 29 (46.3 mg, 94%) as a colorless oil:
[R]2D8 ) +17.4 (c 1.57, CHCl3); IR (thin film) 3390, 2958, 2877,
1
1700, 1523, 1457, 1373, 1241, 1052 cm-1; H NMR (500 MHz,
CDCl3) δ 1.75-1.84 (m, 2 H), 2.05 (s, 3 H), 2.03-2.10 (m, 1 H),
2.07 (dd, J ) 8.2, 15.2 Hz, 1 H), 3.18 (bs, 1 H), 3.40 (bs, 1 H),
3.52 (bs, 1 H), 3.60-3.72 (m, 2 H), 3.81 (d, J ) 9.1 Hz, 1 H),
3.93-4.00 (m, 1 H), 5.07 (d, J ) 12.2 Hz, 1 H), 5.11 (d, J ) 12.2
Hz, 1 H), 5.35-5.40 (m, 1 H), 5.67-5.82 (m, 3 H), 7.29-7.37
(m, 5 H); 13C NMR (125 MHz, CDCl3) δ 21.2, 33.1, 37.2, 49.6,
65.9, 67.0, 68.3, 72.8, 73.0, 126.9, 128.0 (×2), 128.2, 128.5 (×2),
(1R,2S,2′S,2′′E,3S,4R,4′′E,6S,6′′E,8′′R,10′′S,12′′E,14′′R)-4-Ac-
etoxy-2,3-epoxy-6-hydroxy-1-[2′-(8′′,10′′,12′′,14′′-tetramethyl-
hexadeca-2′′,4′′,6′′,12′′-tetraenoylamino)-3′-tert-butyldiphenyl-
4124 J. Org. Chem., Vol. 72, No. 11, 2007

Synthesis of (+)-Scyphostatin
silyloxy-propyl]-2-cyclohexen-1-ol (34). To a solution of 31 (49.6
mg, 78.3 µmol) in MeOH (5.0 mL) at room temperature were added
Pd(OH)2/C (10.2 mg, 17 wt %) and AcOH (0.34 M in MeOH, 0.45
mL, 0.15 mmol). The reaction mixture was stirred at room
temperature for 30 min under a hydrogen atmosphere. Then it was
diluted with EtOAc, and filtered. The insoluble material was washed
with EtOAc. The filtrate was washed with H2O and brine, dried
over Na2SO4, and evaporated to give 31′ as a white crystal. 31′:
1H NMR (500 MHz, CDCl3) δ 1.11 (s, 9 H), 1.43-1.56 (m, 1 H),
1.74-1.84 (m, 1 H), 2.03-2.19 (m, 2 H), 3.16 (d, J ) 3.4 Hz, 1
H), 3.18 (d, J ) 3.4 Hz, 1 H), 3.67-3.94 (m, 4 H), 5.04 (t, J ) 8.2
Hz, 1 H), 7.39-7.50 (m, 6 H), 7.67-7.73 (m, 4 H).
15.1 Hz, 1 H), 5.89 (d, J ) 15.0 Hz, 1 H), 6.05 (dd, J ) 1.6, 9.9
Hz, 1 H), 6.14 (dd, J ) 10.7, 15.1 Hz, 1 H), 6.25 (dd, J ) 11.2,
14.8 Hz, 1 H), 6.53 (dd, J ) 10.7, 14.8 Hz, 1 H), 7.10-7.16 (m,
2 H), 7.32-7.45 (m, 6 H), 7.60-7.67 (m, 4 H); 13C NMR (125
MHz, CD3OD) δ 12.5, 16.4, 20.0, 20.1, 21.5, 21.9, 27.4 (×3), 29.6,
31.7, 35.4, 36.3, 40.0, 45.3, 47.9, 49.2, 49.6, 58.1, 67.3, 77.4, 123.8,
128.8 (×2), 128.9 (×2), 129.4, 129.9, 130.9, 131.0, 132.0, 133.5,
134.2, 134.4, 134.6, 136.7 (×4), 141.4, 142.5, 146.1, 146.2, 168.5,
199.6. FAB+-HRMS (NBA) m/z: [M + H] Calcd for C45H62NO5-
Si, 724.4397; found, 724.4402.
(2′S,2′′E,4S,4′′E,5S,6S,6′′E,8′′R,10′′S,12′′E,14′′R)-4,5-Epoxy-
6-hydroxy-6-[3′-hydroxy-2′-(8′′,10′′,12′′,14′′-tetramethylhexadeca-
2′′,4′′,6′′,12′′-tetraenoylamino)-propyl]-2-cyclohexen-1-one (1).
To a solution of 35 (14.1 mg, 19.5 µmol) in THF (0.5 mL) were
added AcOH (0.17 M in THF, 0.17 mL, 29 µmol) and TBAF (0.090
M in THF, 0.33 mL, 30 µmol) at 0 °C. The reaction mixture was
allowed to gradually warm to room temperature, and stirring was
continued for 9 h. Then it was quenched with saturated NH4Cl,
extracted with EtOAc, washed with H2O and brine, dried over Na2-
SO4, and evaporated. The resulting residue was purified by column
chromatography (neutral silica gel, CH2Cl2/MeOH 20/1) to give 1
(5.7 mg, 61%) as a colorless amorphous powder: [R]2D8 ) +61.9
(c 0.240, CH3OH) [lit.3 [R]25 ) +66.4 (c 0.09, MeOH)]; IR (thin
film) 3289, 2958, 2923, 169D7, 1650, 1608, 1542, 1457, 1376, 1268,
To a solution of the residue and 2 in DMF (2.0 mL) at 0 °C
were added EDCI (20.0 mg, 0.10 mmol) and diisopropylethylamine
(DIPEA) (0.53 M in DMF, 0.14 mL, 64 µmol). The reaction mixture
was allowed to gradually warm to room temperature, and stirring
was continued for 12 h. Then it was quenched with saturated NH4-
Cl and extracted with Et2O. The organic layer was washed with
H2O and brine, dried over Na2SO4, and evaporated. The resulting
residue was purified by column chromatography (neutral silica gel,
CH2Cl2/MeOH 20/1) to give 34 (40.2 mg, 65%) as a colorless oil:
[R]2D7 ) +2.89 (c 0.784, CH3OH); IR (thin film) 3390, 2958,
1
2927, 1747, 1650, 1604, 1427, 1369, 1234, 1110, 1002 cm-1; H
NMR (500 MHz, CD3OD) δ 0.82 (d, J ) 6.6 Hz, 3 H), 0.85 (t, J
) 7.3 Hz, 3 H), 0.90 (d, J ) 6.7 Hz, 3 H), 1.00 (d, J ) 6.6 Hz, 3
H), 1.06 (s, 9 H), 1.13-1.23 (m, 1 H), 1.25-1.39 (m, 4 H), 1.51-
1.61 (m, 1 H), 1.53 (d, J ) 1.2 Hz, 3 H), 1.79 (dd, J ) 7.2, 13.0
Hz, 1 H), 1.89 (dd, J ) 7.2, 13.0 Hz, 1 H), 1.97-2.10 (m, 3 H),
2.00 (s, 3 H), 2.20-2.29 (m, 1 H), 2.29-2.40 (m, 1 H), 3.09 (d, J
) 3.4 Hz, 1 H), 3.19 (dd, J ) 0.5, 3.4 Hz, 1 H), 3.65-3.70 (m, 1
H), 3.66 (dd, J ) 3.8, 10.8 Hz, 1 H), 3.79 (dd, J ) 5.3, 10.8 Hz,
1 H), 4.29-4.36 (m, 1 H), 4.82 (m, 1 H), 5.05 (t, J ) 8.1 Hz, 1
H), 5.70 (dd, J ) 8.6, 15.1 Hz, 1 H), 5.98 (d, J ) 14.9 Hz, 1 H),
6.15 (dd, J ) 10.5, 15.1 Hz, 1 H), 6.27 (dd, J ) 11.1, 14.9 Hz, 1
H), 6.53 (dd, J ) 10.5, 14.9 Hz, 1 H), 7.14 (dd, J ) 11.1, 14.9 Hz,
1 H), 7.33-7.44 (m, 6 H), 7.63-7.70 (m, 4 H); 13C NMR (125
MHz, CD3OD) δ 12.5, 16.4, 20.0, 20.1, 20.9, 21.5, 21.9, 27.5 (×3),
29.5, 31.7, 34.2, 34.3, 35.4, 36.3, 45.2, 48.8, 49.6, 57.5, 60.9, 67.3,
68.2, 69.4, 73.7, 124.1, 128.8 (×2), 128.9 (×2), 129.5, 130.0, 131.0,
131.1, 133.6, 134.2, 134.5, 134.6, 136.8 (×2), 136.9 (×2), 141.3,
142.2, 146.1, 168.7, 171.8. EI-HRMS m/z: calcd for C47H67O7NSi
[M+], 785.4687; found, 785.4720.
1
1157, 1002 cm-1; H NMR (500 MHz, CD3OD) δ 0.82 (d, J )
6.5 Hz, 3 H), 0.85 (t, J ) 7.5 Hz, 3 H), 0.90 (d, J ) 6.5 Hz, 3 H),
0.99 (d, J ) 6.7 Hz, 3 H), 1.01-1.07 (m, 1 H), 1.13-1.23 (m, 1
H), 1.30-1.39 (m, 2 H), 1.53 (d, J ) 1.0 Hz, 3 H), 1.55-1.63 (m,
1 H), 1.79 (dd, J ) 7.3, 13.4 Hz, 1 H), 1.84-1.92 (m, 2 H), 2.07
(dd, J ) 3.4, 14.7 Hz, 1 H), 2.21-2.29 (m, 1 H), 2.29-2.38 (m,
1 H), 3.45 (dd, J ) 5.8, 11.0 Hz, 1 H), 3.51 (dd, J ) 5.1, 11.0 Hz,
1 H), 3.58 (td, J ) 1.7, 3.9 Hz, 1 H), 3.66 (d, J ) 3.9 Hz, 1 H),
4.00-4.08 (m, 1 H), 4.84 (m, 1 H), 5.70 (dd, J ) 8.7, 15.1 Hz, 1
H), 5.89 (d, J ) 15.1 Hz, 1 H), 6.07 (dd, J ) 1.5, 9.9 Hz, 1 H),
6.14 (dd, J ) 10.7, 15.1 Hz, 1 H), 6.25 (dd, J ) 11.2, 14.8 Hz, 1
H), 6.53 (dd, J ) 10.7, 14.8 Hz, 1 H), 7.09-7.17 (m, 2 H); 13C
NMR (125 MHz, CD3OD) δ 12.5, 16.4, 19.9, 21.5, 21.9, 29.5, 31.7,
35.4, 36.3, 39.8, 45.2, 48.0, 49.2, 49.6, 58.2, 65.6, 77.5, 123.8,
129.4, 130.0, 132.1, 133.6, 134.2, 141.4, 142.4, 145.9, 146.2, 168.6,
199.6. FAB+-HRMS (NBA) m/z: [M + H] calcd for C29H44NO5,
486.3219; found, 486.3217.
Acknowledgment. We are in debt to the Natural Science
Center for Basic Research and Development (N-BARD),
Hiroshima University, for machine time on NMR (JEOL JMN-
LA500), MS (JEOL SX-102A), elemental analysis (Perkin-
Elmer 2400CHN-II), and optical rotation (JASCO DIP-370)
instruments. We thank Dr. Yoshikazu Hiraga for NMR mea-
surements (JEOL JMN-LA500) at the Hiroshima Prefectural
Institute of Science and Technology. We thank Dr. Satoshi
Kojima for prereading the manuscript. Financial support of this
work through Grants-in-Aid for Scientific Research (No.
11740355 and No. 14740349) provided by the Japan Society
for the Promotion of Science is heartily acknowledged.
(2′S,2′′E,4S,4′′E,5S,6S,6′′E,8′′R,10′′S,12′′E,14′′R)-4,5-Epoxy-
6-hydroxy-6-[2′-(8′′,10′′,12′′,14′′-tetramethylhexadeca-2′′,4′′,6′′,-
12′′-tetraenoylamino)-3′-tert-butyldiphenylsilyloxy-propyl]-2-
cyclohexen-1-one (35). (COCl)2 (0.23 M in CH2Cl2, 0.30 mL, 69.0
µmol) was slowly added to a solution of DMSO (0.28 M in CH2-
Cl2, 0.40 mL, 0.11 mmol) in CH2Cl2 (1.0 mL) at -78 °C. After
the mixture was stirred at -78 °C for 30 min, 34 (38.2 mg, 48.6
µmol) in CH2Cl2 (1.5 mL) was added at -78 °C. The reaction
mixture was stirred at -78 °C for 1 h. To the solution was added
Et3N (0.20 mL, 1.4 mmol) at -78 °C. After the mixture was stirred
at -78 °C for 1 h, the reaction was quenched with saturated NH4-
Cl, warmed to room temperature, and extracted with CH2Cl2. The
organic layer was washed with H2O and brine, dried over Na2SO4,
and evaporated. The resulting residue was purified by column
chromatography (neutral silica gel, CH2Cl2/MeOH 20/1) to give
recovered 34 (12.1 mg, 32%) and 35 (17.1 mg, 49%) as a colorless
oil: [R]2D7 ) + 12.7 (c 1.41, CH3OH); IR (thin film) 3070, 2958,
Note Added after ASAP Publication. There was an error
in the abstract and TOC graphic in the version published ASAP
May 4, 2007; the corrected version was published ASAP May
7, 2007.
1
2857, 1697, 1647, 1604, 1427, 1110, 1002 cm-1; H NMR (500
MHz, CD3OD) δ 0.82 (d, J ) 6.6 Hz, 3 H), 0.85 (t, J ) 7.3 Hz,
3 H), 0.90 (d, J ) 7.3 Hz, 3 H), 0.97-1.06 (m, 1 H), 1.00 (d, J )
6.6 Hz, 3 H), 1.02 (s, 9 H), 1.13-1.23 (m, 1 H), 1.25-1.39 (m, 2
H), 1.53 (d, J ) 1.2 Hz, 3 H), 1.56-1.63 (m, 1 H), 1.76-1.92 (m,
3 H), 2.13 (dd, J ) 2.8, 14.6 Hz, 1 H), 2.21-2.29 (m, 1 H), 2.30-
2.40 (m, 1 H), 3.54 (td, J ) 1.6, 3.9 Hz, 1 H), 3.56 (dd, J ) 6.1,
9.9 Hz, 1 H), 3.62 (dd, J ) 5.4, 9.9 Hz, 1 H), 3.64 (d, J ) 3.9 Hz,
1 H), 4.15-4.23 (m, 1 H), 4.82-4.85 (m, 1 H), 5.70 (dd, J ) 8.6,
Supporting Information Available: General experimental
methods, experimental procedures and/or characterization data of
13-18, 23-26, 32, and 36, copies of NMR spectra of new
compounds, and a comparison table of the NMR data of natural
and synthetic scyphostatin and 18. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO070337K
J. Org. Chem, Vol. 72, No. 11, 2007 4125