Enantiocontrolled synthesis of the epoxycyclohexenone moieties of scyphostatin, a potent and specific inhibitor of neutral sphingomyelinase

Article abstract of DOI:10.1016/j.tet.2005.10.082

The epoxycyclohexenone moieties 2 and 3b of scyphostatin (1), a potent and specific inhibitor of neutral sphingomyelinase, were synthesized in enantiomerically pure forms starting from (-)-quinic acid (11). The synthetic method features (i) the preparatio

Full text of DOI:10.1016/j.tet.2005.10.082

Tetrahedron 62 (2006) 1590–1608
Enantiocontrolled synthesis of the epoxycyclohexenone moieties
of scyphostatin, a potent and specific inhibitor
of neutral sphingomyelinase
b
c
c
a
Tadashi Katoh,a, Takashi Izuhara, Wakako Yokota, Munenori Inoue, Kazuhiro Watanabe,
*
Ayaka Nobeyamaa and Takeyuki Suzukia
aDepartment of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima,
Aoba-ku, Sendai 981-8558, Japan
bDepartment of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan
cSagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
Received 26 September 2005; accepted 25 October 2005
Available online 28 November 2005
Abstract—The epoxycyclohexenone moieties 2 and 3b of scyphostatin (1), a potent and specific inhibitor of neutral sphingomyelinase, were
synthesized in enantiomerically pure forms starting from (K)-quinic acid (11). The synthetic method features (i) the preparation of the olefin
masked enones 25 and 29, the precursors for the key aldol-type coupling reaction, (ii) the efficient and stereocontrolled aldol-type coupling
reactions between 25 (or 29) and benzaldehyde (8) and Garner’s aldehyde analogue 9 to deliver alcohols 23 and 24, respectively, both
of which possess the requisite asymmetric quaternary carbon center at the C6 position, and (iii) the stereospecific SN2-type epoxide ring
formation of the mesylates 35 and 47 under mild basic conditions to produce the targeted compounds 2 and 3b, respectively.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of Trichopeziza mollissima SANK 13892.7,8 This natural
product was found to be a powerful and specific inhibitor of
membrane-bound neutral sphingomyelinase (N-SMase).8 It
has been reported that 1 inhibits N-SMase and acidic SMase
(A-SMase) with IC50 values of 1.0 and 49.3 mM, respect-
ively.7,8 Remarkably, scyphostatin is the most potent and
specific one among the many low molecular weight
N-SMase inhibitors of natural sources9 or of synthetic
substances10 known to date.
Recently, sphingomyelinase (SMase) inhibitors have received
considerable attention from the biological and pharmacuetical
standpoints.1 SMaseistheenzyme thatspecificallyhydrolyzes
the phosphoester linkage of sphingomyelin (SM), one of the
most abundant sphingolipid species, to generate ceramide and
phoshocholine.2,3 The SM-derived ceramide is believed to be
an intracellular lipid second messenger in cell membranes and
to play important roles in the regulation of cell proliferation,
differentiation, and apoptosis.2,3 SMase inhibitors, therefore,
are considered as valuable tools for the investigation of the
biological function of the enzyme and the catabolite ceramide
in signal transduction.3 In addition, selective SMase inhibitors
are highly anticipated to be promising candidates for the
treatment of ceramide-mediated pathogenic states such as
AIDS,4 inflammation,5 and immunological and neurological
disorders.6
In 1997, Ogita et al. at the Sankyo research group reported
the isolation and structure elucidation of a novel natural
product, scyphostatin (1, Fig. 1), from the mycelial extract
Keywords: Sphingomyelinase; Aldol-type coupling; Diels–Alder reaction.
*
Corresponding author. Tel.: C81 22 234 4183; fax: 81 22 275 2013;
e-mail: katoh@tohoku-pharm.ac.jp
Figure 1. Structures of scyphostatin (1) and the epoxycyclohexeone
moieties 2 and 3b.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.082

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1591
The gross structure of scyphostatin (1) was revealed by
extensive and incisive spectroscopic studies.7 It consists of a
novel, highly oxygenated cyclohexenone ring incorporated
with a C-20 unsaturated fatty acid-substituted aminopropanol
side chain. This initial structure elucidation only established
the relative and absolute stereochemistry of the cyclohex-
enone moiety of 1.7 In 2001, Kogen et al. at the Sankyo
research group determined the relative and absolute configur-
ations of the three stereogenic centers present in the fatty acid
side chain.11 At the almost same time, Hoye et al. disclosed an
enantioselective synthesis of the C-20 unsaturated fatty acid
moiety and provided alternative proof of its stereostructure
including the absolute configuration.12
The remarkable biological properties and unique structural
features make 1 an exceptionally intriguing and timely
target for total synthesis. So far, a number of synthetic
approaches toward scyphostatin (1) have been reported
by Gurujar’s group,13 Taylor’s group,14 Ohkata’s group,15
Kita’s group,16 Maier’s group,17 Negishi’s group,18 and
Pitsino’s group.19 We have already reported our own
preliminary results concerning the enantioselective syn-
thesis of the epoxycylohexenone substructures 2 and 3b20
(Fig. 1). Additionally, we have also disclosed an efficient
method for the introduction of a fatty acid side chain at the
amino propanol moiety.21 In 2004, our assiduous endeavors
culminated in the completion of the first total synthesis of
(C)-1.22 In this paper, we wish to disclose the full details of
our first-generation synthesis of the epoxycyclohexenone
moieties 2 and 3b of scyphostatin (1).
Scheme 1. Primary synthetic plan for the epoxycyclohexeone moieties 2
and 3a.
2.2. Synthesis of the intermediate 10
At first, as shown in Scheme 2, we pursued the synthesis of
the intermediate 10, a substrate for the key aldol-type
coupling reaction, starting from commercially available
(K)- quinic acid (11). The known cyclohexanone 1224 was
2. Results and discussion
2.1. Primary synthetic plan for the epoxycyclohexenone
moieties 2 and 3a
Our primary synthetic plan for the epoxycyclohexenone
moieties 2 and 3a is outlined in Scheme 1. The key feature of
this plan is aldol-type coupling reactions between the
cyclohexenone 10 and the aldehydes 8 and 9 to form the
coupling products 6 and 7, respectively (10C8/6 and 10C
9/7). In these reactions, we envisioned that electrophiles 8
and 9 would approach exclusively from the less hindered
a-face of the enolate, generated in situ from 10, under the
influence of the b-oriented O-isopropylidenedioxy moiety,
thus leading to establishment of the requisite asymmetric
quaternary carbon center at the C6 position (cyclohexeneone
numbering)23 in 6 and 7. This type of coupling reaction is
considerably challenging at the synthetic chemistry level,
because the substrate 10 possesses unusual trihydroxy
functionalities at the C4, C5, and C6 positions, and in addition,
an electrophilic enone system. The coupling products 6 and 7
would be converted to the target molecules 2 and 3a through
the advanced key intermediates 4 and 5, respectively, by
sequential functional group manipulation and deprotection, or
vice versa; the sequence involves deoxygenation of the
secondary hydroxy group in the side chain and stereospecific
SN2-type epoxide ring formation as the crucial steps. The
cyclohexenone 10 having three contiguous oxygen function-
alities at the C4, C5, and C6 positions with correct
stereochemistries would be derived from commercially
available (K)-quinic acid (11).
Scheme 2. Synthesis of the intermediate 10. (a) TBSCL, imidazole, DMF,
rt, 98%; (b) NaBH4, THF–H2O, K5 8C/rt, 53% for 14, 44% for 15;
(c) Ac2O, pyridine, DMAP, 0 8C/rt, 98%; (d) DEAD, Ph3P, benzonic
acid, THF, 0 8C/98%; (e) 2 M KOH–MeOH, rt, quant.; (f) DEAD, Ph3P,
THF, rt, 67% for 15/17, 0% for 14/17; (g) mCPBA, NaHCO3, CH2Cl2,
0 8C/rt, 92%; (h) Se2Ph2, NaBH4, EtOH, 0 8C/reflux; H2O2, THF,
0 8C/reflux, 78%; (i) Dess–Martin periodinane, CH2Cl2, rt, 95%.

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T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
readily and sufficiently prepared from 11 in three steps [(1)
dimethoxypropane/p-TsOH/acetone, reflux, 80%; (2)
LiAlH4/THF, reflux, quant.; (3) NaIO4/t-BuOH–THF–
AcOH, room temperature, quant.] according to the reported
procedure.24 After protection of the hydroxy group in 12 as
its t-butyldimethylsilyl (TBS) ether, the carbonyl function
of the resulting TBS ether 13 was subjected to reduction
with sodium borohydride to furnish an epimeric mixture of
the alcohols 14 (53%) and 15 (44%) that were separated by
silica gel column chromatography. The newly formed C2
stereochemistry of the two isomers was assigned on the
basis of spectroscopic studies. The NOESY experiment of
the acetate 16 derived from 14 showed a clear interaction
between C2–H and C4–H.
phenylselenide, which was then oxidized by excess 30%
aqueous hydrogen peroxide to provide the allyl alcohol 19
in 95% overall yield via elimination of the intermediary
phenylselenoxide. Finally, Dess–Martin oxidation27 of 19
furnished the requisite intermediate 10 in 95% yield.
2.3. Initial attempts to achieve the coupling reaction
of the cyclohexenone 10 with benzaldehyde (8)
Having obtained the intermediate 10, we next investigated
the crucial aldol-type coupling reaction between 10 and
benzaldehyde (8) as shown in Scheme 3. Initial attempts to
achieve this coupling reaction, unfortunately, turned out to
be fruitless. Thus, reaction of the lithium enolate of 10,
generated in situ by reaction with LiN(SiMe3)2, with 8 in
THF at K78 8C resulted in the predominant formation of the
unexpected dimerized product 20 (38%) as a single stereo
isomer and the desired coupling product 21 (12%) as an
epimeric mixture with respect to the benzilic hydroxy
group. Since the coupling product 21 was very unstable
during isolation and purification by silica gel column
chromatography, assignment of the structure and stereo-
chemistry of 21 was performed by spectroscopic analyses
(COSY, HMBC, and NOESY experiments) of the corre-
sponding carbonyl compound 22, readily prepared by Dess–
Martin oxidation (78%).
We next examined installation of an olefinic double bond by
dehydration of 14 and 15. Thus, reaction of 15 with diethyl
azodicarboxylate (DEAD) and triphenylphosphine provided
the desired olefin 17 in 67% yield with complete
regioselectivity at the C1–C2 position. On the contrary,
treatment of the C2 epimeric alcohol 14 under the same
dehydration conditions afforded none of the desired olefinic
product 17, and the unreacted starting material 14 was
recovered unchanged. Therefore, the alcohol 14 was
converted to 15 by employing the Mitsunobu inversion
procedure25 (98% overall yield). The difference of the
reactivity between 14 and 15 under the dehydration
conditions can be rationalized by conformational analyses
of both 14 and 15 (Fig. 2). Thus, the NOESY experiment of
15 indicated that the cyclohexane ring takes a boat-form,
which places the C2 hydroxy group in an axial position; this
conformation may facilitate E2 elimination to afford the
desired D1,2 olefin 17. On the other hand, the NOESY
experiment of 14 indicated that the C2 hydroxy group is in
equatorial orientation within the boat-formed cyclohexane
ring; this conformation would preclude any possibility of
E2 elimination.
Scheme 3. Aldol-type coupling reaction of the cyclohexenone 10 and
benzaldehyde (8). (a) LiN(SiMe3)2, THF, K78 8C, 38% for 20, 12% for 21;
(b) Dess–Martin periodinane, CH2Cl2, rt, 78%.
These preliminary studies demonstrated that the enone
olefin function present in 10 was extremely susceptible to
nucleophilic attack of the enolate generated from 10 itself.
In order to circumvent this problem, we decided to mask the
highly reactive enone system of 10 in the form of the bromo
ether 25 (cf. Scheme 4) during the aldol-type coupling
reaction. We anticipated that 25 would behave as a
promising substrate for the designed coupling reaction.
Further investigations concerning the synthesis of 25 and
subsequent coupling reaction with the aldehydes 8 and 9 are
the subject of the following sections.
Figure 2. Conformational analyses of the alchohols 14 and 15.
To continue the synthesis, the olefin 17 was oxidized with
m-chloroperbenzoic acid (mCPBA) to give the epoxide 18
as
a single diastereomer in 92% yield, whose
stereochemistry was assigned based on the NOE exper-
iment. The stereoselectivity can be explained by the
consideration that the oxidizing reagent (mCPBA) accessed
exclusively from the less hindered a-face of the molecule
under the influence of the b-oriented O-isopropylidenedioxy
moiety. Conversion of the epoxide 18 to the allyl alcohol 19
was successfully achieved by employing a reliable
Sharpless protocol.26 Thus, treatment of 18 with the
phenylselenyl anion, generated in situ from diphenyl
diselenide and sodium borohydride, caused the regioselec-
tive epoxide ring opening at the sterically and electro-
statically favored C2 position to form the corresponding
2.4. Modified synthetic plan for the epoxycyclohexenone
moieties 2 and 3a
Our initial attempts to achieve the direct coupling between
the cyclohexenone 10 and benzaldehyde (8) met with
failure; therefore, we settled on modifying our original
synthetic plan. Thus, as shown in Scheme 4, the bromo ether

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1593
Scheme 4. Modified synthetic plan for the epoxycyclohexenone moieties 2
and 3.
25, a synthetically equivalent of the cyclohexenone 10, was
envisaged to be prepared by Diels–Alder reaction of 10 with
cyclopentadiene (26) followed by desilylation and bromo
etherification. The crucial aldol-type reaction of 25 with the
aldehydes 8 and 9 would produce the coupling products 23
and 24, respectively, with correct stereochemistry at the C6
position. The intermediates 23 and 24 would be converted to
the cyclohexenones 4 and 5, the potential key intermediates
of the target molecules 2 and 3, via sequential functional
group manipulation. As will be mentioned later (cf. Sections
2.7 and 2.8), the N,O-isopropylidene group at the C6 side
chain in 24 turned out to be labile during the regeneration of
the enone olefin moiety (cf. 24/5a); therefore, the
N,O-isopropylidene group was replaced with a sturdy cyclic
carbamate group (cf. 5b).
Scheme 5. Aldol-type coupling reaction of the masked enone 25 with
benzaldehyde (8) and the synthesis of the intermediate 31. (a) Et2AlCl,
CH2Cl2, K78/0 8C, 97%; (b) TBAF, THF, 0 8C/rt, 75%; (c) NBS,
CH2Cl2, 0 8C/rt, 86%; (d) LiN(SiMe3)2, THF, 98%; (e) LiN(SiMe3)2,
THF, K78 8C; at K78 8C add. benzaldehyde (8), 98%; (f) LiN(SiMe3)2,
THF, K78 8C; at K78 8C add. benzaldehyde (8), 98%; (g) phenyl
chlorothionoformate, DMAP, MeCN, rt, 92%; (h) n-Bu3SnH, AIBN,
toluene, 110 8C, 79%.
The crucial aldol-type coupling reaction between 2529 and
benzaldehyde (8) was next conducted to establish the
requisite C6 asymmetric quaternary carbon center. During
the optimization of the reaction conditions, we found that
the bromo ether 25 exhibited an interesting and unprece-
dented reactivity. Thus, treatment of 25 with 1.1 equiv of
LiN(SiMe3)2 in THF at K78 8C for 30 min resulted in the
formation of the unexpected cyclopropane derivative 29 in
almost quantitative yield (98%), whose structure was
confirmed by extensive spectroscopic studies including
COSY, HMBC, and NOESY experiments in the 500 MHz
NMR spectra. Subsequent treatment of 29 with 1.1 equiv of
LiN(SiMe3)2 in THF at K78 8C followed by addition of
benzaldehyde (8) (2.2 equiv) afforded the desired coupling
product 30 in excellent yield (98%) as a hardly separable
mixture of the epimeric alcohols (6:1 by 500 MHz 1H
NMR). The C6 stereochemistry of the product 23 turned out
to be completely controlled as we expected; the assignment
was later confirmed by NOE study of the transformed
compound 31 (vide infra).
2.5. Synthesis of the intermediate 31 for the epoxycyclo-
hexenone moiety 2: preparation of the masked enone 25
and subsequent aldol-type coupling reaction with benz-
aldehyde (8)
As shown in Scheme 5, we next carried out the synthesis
of the intermediate 31 for the first target compound 2;
the sequence involved the preparation of the olefin
masked cyclohexenone 25 and subsequent coupling
reaction with benzaldehyde (8) as the crucial steps.
Diels–Alder reaction of 10 with cyclopentadiene (26) in
the presence of diethylaluminium chloride proceeded
smoothly and cleanly in a completely diastereofacial- and
endo-selective manner to provide the corresponding
cycloadduct 27 as a single isomer in almost quantitative
yield (97%). The structure and stereochemistry of the
Diels–Alder adduct 27 was assigned based on the NMR
spectral analysis including NOESY experiments; thus,
clear NOE interactions between C9–H and C8a–H,
C4a–H and between C3–H and C7–H were observed,
respectively. After deprotection of the TBS group of 27
with tetrabutylammonium fluoride (TBAF) (75%), the
resulting alcohol 28 was subjected to bromo etherifica-
tion using N-bromosuccinimide (NBS)28 to provide the
desired tetracyclic bromo ether 25 in 86% yield.
Encouraged by these successful results, we next examined a
more efficient one-pot procedure for the direct coupling of
25 and 8. Thus, treatment of 25 with 2.2 equiv of
LiN(SiMe3)2 followed by reaction with 2.2 equiv of 8
furnished the requisite coupling product 23 in 98% yield.
The secondary hydroxy group in 23 was deleted by using
Robin’s modification30 of the Barton method.31 Thus,
treatment of 23 with phenyl thionochloroformate in
acetonitrile in the presence of 4-dimethylaminopyridine
(DMAP) at ambient temperature afforded the corresponding
phenoxythionocarbonate 30 in 92% yield. Compound 30

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was then allowed to react with tri-n-butyltin hydride in
toluene in the presence of a catalytic amount of 2,20-
azobisisobutyronitrile (AIBN) at 110 8C, giving rise to the
desired deoxygenated product 31 in 79% yield. At this
stage, the C6 stereochemistry could be unambiguously
confirmed by NOESY experiments in the 500 MHz 1H
NMR spectrum of 31, in which a clear NOE interaction
between C5–H and the benzylic proton was observed.
The remaining task to complete the synthesis of the first
target compound 2 involved the critical epoxide ring
formation utilizing the two oxygen functionalities at the
C4 and C5 positions in 34. Toward this end, mesylation of
the hydroxy group in 34 under the standard conditions
(MsCl, Et3N, DMAP, CH2Cl2, 0 8C/room temperature)
(85%) followed by hydrolysis of the acetonide moiety of the
resulting mesylate 4 by treatment with aqueous trifluoro-
acetic acid (TFA), furnished the desired diol 35 in 85%
yield. Finally, the expected epoxide ring formation was
successfully achieved by brief exposure of 35 to 0.2 M
sodium hydroxide in ether at 0 8C for 10 min, providing the
epoxycyclohexenone moiety 2 in 90% yield.
2.6. Synthesis of the epoxycyclohexenone moiety 2
Having succeeded in introduction of the benzyl substituent
at the C6 position with the correct stereochemistry, we next
executed conversion of 31 into the epoxycyclohexenone
moiety 2 (Scheme 6); the sequence involved regeneration of
the enone system and subsequent epoxide ring formation as
the pivotal steps. Regioselective cleavage of the cyclopro-
pane ring in 31 was successfully achieved by treatment with
trimethylsilyl iodide (TMSI)32 in carbon tetrachloride at
K20/K10 8C to give the desired g-iodo ketone 32 in 89%
yield as the sole product. The regioselectivitiy observed for
this ring opening reaction can be explained by the so-called
stereoelectronic effect. Thus, the sC2–C7 orbital efficiently
overlaps with the pC]O orbital, while the overlap between
the sC2–C10 orbital and the pC]O orbital is insufficient due
to the geometrical factor. An attack of the iodo anion,
therefore, occurred predominantly at the C7 position in 31.
Conversion of the g-iodo ketone 32 to the requisite
cyclohexenone 34 was effectively achieved by applying
the Ogasawara procedure.28 Thus, treatment of 32 with zinc
powder in methanol containing a small amount of acetic
acid gave the tricyclic compound 33 in 91% yield, which
was then subjected to retro-Diels–Alder reaction by heating
at 230 8C in diphenyl ether to produce 34 in 81% yield.
2.7. Initial attempts on the synthesis of the fully
functionalized epoxycyclohexenone moiety 3a
Having established the synthetic route to the epoxycyclo-
hexenone moiety 2, we next undertook the synthesis of the
fully functionalized epoxycyclohexenone moiety 3a (cf.
Scheme 4), which possesses the N,O-protected amino
propanol side chain and the requisite asymmetric carbon
centers. We envisaged that the targeted compound 3a would
be elaborated starting from the bromo ether 25 and D-serinal
derivative 933 [(R)-N-(p-toluenesulfonyl)-N,O-isopropyli-
dene serinal], readily accessible from D-serine, based on
the explored synthetic route to the epoxycyclohexenone
moiety 2.
As shown in Scheme 7, the synthesis started with the crucial
aldol coupling reaction between 25 and 9. The enolate
anion, generated in situ by treatment of 25 with
LiN(SiMe3)2 (2.2 equiv) in THF at K78 8C, was allowed
to react with 9 (2.5 equiv) to furnish an excellent yield
Scheme 7. Initial attempts on the synthesis of the intermediate 41 for the
epoxycyclohexenone moiety 3a. (a) LiN(SiMe3)2, THF, K78 8C; at
K78 8C, add. (R)-N-(p-toluenesulfonyl)-N,O-isopropylidene serinal (9),
98%; (b) NaN(SiMe3)2, THF, K78 8C; CS2, K78/K50 8C; MeI,
K78/K50 8C, 88%; (c) n-Bu3SnH, Et3B, toluene, rt, 95%; (d) TMSI,
CCl4, K10 8C, 91%; (e) 2,2-dimethoxypropane, p-TsOH, benzene, 60 8C,
83%; (f) Zn, AcOH, MeOH, 60 8C, 98%; (g) Ph2O, 230 8C, 25%.
Scheme 6. Synthesis of the epoxycyclohexenone moiety 2. (a) TMSI, CCl4,
K20/K10 8C, 89%; (b) Zn, AcOH, MeOH, 60 8C, 91%; (c) Ph2O,
230 8C, 81%; (d) MsCl, Et3N, DMAP, CH2Cl2, 0 8C/rt, 85%; (e) TFA,
H2O, 0 8C, 85%; (f) 0.2 M NaOH, Et2O, 0 8C, 90%.

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1595
(98%) of the desired coupling product 24 as an inseparable
mixture of the epimeric alcohols (9:1 by 500 MHz 1H
NMR). Removal of the hydroxy group in 24 was initially
attempted by employing the same reaction conditions
[ClC(S)OPh, DMAP, MeCN] described for the preparation
of 30 from 23 (cf. Scheme 5), which, unfortunately, ended in
failure and the starting material 24 was recovered
unchanged even under heating conditions. This is pre-
sumably due to the steric hindrance around the hydroxy
group in 24. Therefore, we looked at the Barton procedure31
to achieve the requisite deoxygenation of the sterically
hindered hydroxy group. Employing the original Barton
conditions (NaH, CS2, THF; MeI, 0 8C/room tempera-
ture), the reaction gave a poor yield (w30%) of the desired
methyl xanthate 36. In order to improve the yield, some
modifications were made of the reaction conditions. After
several trials, to our delight, we found that treatment of 24
with NaN(SiMe3)2 (1.2 equiv) in THF at K78 8C followed
by addition of carbon disulfide (10 equiv) and iodomethane
(10 equiv) at the same temperature furnished the methyl
xanthate 36 in 88% yield. The resulting methyl xanthate 36
was further treated with tri-n-butyltinhydride and triethyl-
borane34 in toluene at ambient temperature to afford the
requisite deoxygenated product 37 in 95% yield.
Scheme 8. Synthesis of the intermediate 46 for the epoxycyclohexenone 3.
(a) 1.0 M HCl, THF, 55 8C; (b) phosgen dimer, pyridine, THF, rt, 67% (two
steps); (c) TMSI, CCl4, K20 8C, 74%; (d) Zn, AcOH, MeOH, 60 8C, 95%;
(e) Ph2O, 230 8C, 59%.
With the intermediate 37 possessing the requisite N,O-pro-
tected amino propanol side chain and the correct stereo-
chemistry in hand, our next efforts were devoted to
regeneration of the cyclohexenone olefin moiety. Toward
this end, regioselective cleavage of the cyclopropane ring in
37 was conducted by treatment with TMSI to give the iodo
ether 38 in 91% yield. In this reaction, the N,O-
isopropylidene group was simultaneously hydrolyzed;
therefore, regeneration of the N,O-isopropylidene moiety
of the resulting aminopropanol 38 was carried out under
conventional conditions (2,2-dimethoxypropane, p-TsOH,
benzene, 60 8C) to furnish the acetonide 39 in 83% yield.
Further treatment of 39 with zinc powder in methanol
containing acetic acid at 60 8C furnished the tricyclic
compound 40 in 98% yield. Retro-Diels–Alder reaction of
40 by the thermolysis at 230 8C in diphenyl ether, to our
disappointment, provided a poor yield (25%) of the
cyclohexenone derivative 41. This is presumably due to
the instability of the N,O-isopropylidene group under the
harsh reaction conditions. Fortunately, this problem was
solved by replacement of the N,O-isopropylidene group
with a robust cyclic carbamate group prior to subjection to
the retro-Diels–Alder reaction (cf. Scheme 8). This is the
subject of the following section.
(trichloromethyl chloroformate) in the presence of pyridine
in THF, providing the desired cyclic carbamate 43 in 67%
yield for the two steps.
To forward the synthesis, regeneration of the cyclohexenone
olefin moiety was next investigated. Thus, regioselective
cleavage of the cyclopropane ring in 43 by reaction with
TMSI afforded the expected iodide 44 in 74% yield. Further
treatment of 44 with zinc powder in methanol containing
acetic acid furnished the alcohol 45 in 95% yield. Retro-
Diels–Alder reaction of 45 proceeded effectively by
thermolysis at 230 8C in diphenyl ether. The desired
cyclohexenone 46 was obtained in an acceptable 59% yield.
The final route that led to completion of the synthesis of the
targeted molecule 3 is summarized in Scheme 9. The
hydroxy group in 46 was mesylated under standard
conditions (MsCl, Et3N, DMAP, CH2Cl2, 0 8C/room
2.8. Successful synthesis of the fully functionalized
epoxycyclohexenone moiety 3b
The synthesis of the fully functionalized epoxycyclo-
hexenone moiety 3b was successfully achieved by
exchanging the N,O-isopropylidene moiety in 37 with the
corresponding cyclic carbamate functionality. Thus, as
shown in Scheme 8, the N,O-isopropylidene moiety in 37
was selectively deprotected by exposure to aqueous
hydrogen chloride in THF at 55 8C, which furnished an
equilibrium mixture of the N-Ts-b-amino alcohol 42a and
the cyclic hemiacetal 42b (ca. 1:1 by 1H NMR). This
equilibrium mixture was then treated with phosgene dimer
Scheme 9. Synthesis of the intermediate 3b. (a) MsCl, Et3N, DMAP,
CH2Cl2, 0 8C/rt, 83%; (b) TFA, H2O, 0 8C, quant.; (c) 0.2 M NaOH,
Et2O, 0 8C, 75%.

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temperature) to give the corresponding mesylate 5 in 83%
yield. The O-isopropylidene moiety of 5 was then
hydrolyzed by reaction with aqueous trifluoroacetic acid at
0 8C to provide the requisite diol 47 in quantitative yield.
Finally, brief exposure of 47 to aqueous sodium hydroxide
in ether at 0 8C, led to the formation of 3b in 75% yield. The
structure and stereochemistry of 3b were unambiguously
confirmed by single X-ray crystallographic analysis as
depicted in Figure 3.35
were freshly distilled from sodium/benzophenone under
argon. Dichloromethane, acetonitrile, and N,N-dimethyl-
formamide (DMF) were distilled from calcium hydride
under argon.
Melting points were taken on a Yanaco MP-3 micro melting
point apparatus and are uncorrected. Measurements of
optical rotations were performed with a JASCO P-1020
automatic digital polarimeter. 1H and 13C NMR spectra
were measured with a Brucker DRX-500 (500 MHz)
spectrometer or a Brucker DRX-250 (250 MHz). Chemical
shifts were expressed in ppm using tetramethylsilane (dZ0)
as an internal standard. The following abbreviations are
used: singlet (s), doublet (d), triplet (t), multiplet (m),
and broad (br). Infrared (IR) spectral measurements
were carried out with a JASCO FT/IR-5300 spectrometer.
Low-resolution mass (MS) spectra was measured on
Shimadzu GCMS-QP2010. High-resolution mass (HRMS)
spectra was measured on JEOL MStation JMS-700 mass
spectrometer. Elemental analyses were performed with a
Perkin Elmer 2400II apparatus.
4.1.1. (1R,2R,3R)-3-tert-Butyldimethylsiloxy-1,2-(O-iso-
propylidenedioxy)cyclohexan-5-one (13). tert-Butyldi-
methylsilyl chloride (24.4 g, 0.16 mol) was added to a
stirred solution of 1224 (10.0 g, 54 mmol) in dry DMF
(120 ml) containing imidazole (14.7 g, 0.22 mol) at room
temperature. After 15 h, the mixture was diluted with ethyl
acetate (800 ml). The organic layer was successively
washed with 3% aqueous hydrochloric acid (2!250 ml),
saturated aqueous sodium hydrogen carbonate (2!250 ml),
and brine (2!250 ml), then dried over Na2SO4. Concen-
tration of the solvent in vacuo afforded a residue, which was
purified by column chromatography (hexane/ethyl acetate,
14:1) to give 13 (16.2 g, 98%) as a colorless oil. [a]D20
Figure 3. X-ray structure of the epoxycyclohexenone moiety 3b. Red, O;
navy, N; yellow, S; blue, H.
3. Conclusion
In conclusion, we have succeeded in developing an efficient
and enantioselective synthetic pathway to the epoxycyclo-
hexenone moieties 2 and 3b of scyphostatin (1). The
explored method features (i) the preparation of the key
intermediate cyclohexene 10 and its olefin masked enone 25
starting from commercially available (K)-quinic acid (11),
(ii) the aldol-type coupling reaction of the ketone 25 with
benzaldehyde (8) or Garner’s aldehyde analogue 9 to install
the requisite asymmetric quaternary carbon center at the C6
position with complete stereoselectivity (25C8/23 and
25C9/24), and (iii) the facile epoxide ring formation of
the b-hydroxymesylates 35 and 47 under mild basic
conditions (35/2 and 47/3b). Further investigation
toward the synthesis of scyphostatin analogues based on
the present study is now in progress and will be reported in
due course.
1
C105.3 (c 1.00, CHCl3); H NMR (500 MHz, CDCl3) d
0.05 (3H, s, Si-Me), 0.09 (3H, s, Si-Me), 0.83 (9H, s, Si-t-
Bu), 1.35 (3H, s, C-Me), 1.42 (3H, s, C-Me), 2.37 (1H, ddd,
JZ1.9, 3.5, 17.5 Hz, C4–H), 2.64 (1H, dd, JZ2.2, 17.4 Hz,
C4–H), 2.65 (1H, dd, JZ2.5, 17.5 Hz, C6–H), 2.75 (1H, dd,
JZ3.5, 17.5 Hz, C6–H), 4.16 (1H, m, C3–H), 4.22 (1H, dt,
JZ2.2, 7.2 Hz, C2–H), 4.69 (1H, m, C1–H); 13C NMR
(125 MHz, CDCl3) d K5.06, K5.04, 17.9, 23.9, 25.6 (3
carbons), 26.3, 40.1, 41.9, 68.7, 72.4, 75.1, 108.7, 207.7; IR
(neat) 440, 520, 690, 780, 810, 840, 870, 910, 980, 1010,
1060, 1090, 1140, 1180, 1210, 1250, 1380, 1470, 1720,
2860, 2930, 2960 cmK1; HREIMS (m/z) calcd for
C14H25O4Si [(MKMe)C]: 285.1522, found 285.1253.
4. Experimental
4.1.2. (1R,2R,3R,5R)- and (1R,2R,3R,5S)-3-tert-Butyl-
dimethylsiloxy-5-hydroxy-1,2-(O-isopropylidenedioxy)-
cyclohexane (14) and (15). Sodium borohydride (1.30 g,
34 mmol) in water (15 ml) was added dropwise to a stirred
solution of 13 (9.40 g, 31 mmol) in THF (400 ml) at K5 8C,
and stirring was continued for 1 h at room temperature. The
reaction was quenched with saturated aqueous ammonium
chloride (30 ml) at 0 8C, and then the mixture was diluted
with ethyl acetate (1000 ml). The organic layer was washed
with saturated aqueous ammonium chloride (2!300 ml)
and brine (2!300 ml), then dried over Na2SO4. Concen-
tration of the solvent in vacuo gave a residue, which was
separated by column chromatography (hexane/ethyl acetate,
4.1. General methods
All reactions involving air- and moisture-sensitive reagent
were carried out using oven-dried glassware and standard
syringe-septum cap techniques. Routine monitorings of
reaction were carried out using glass-supported Merck silica
gel 60 F254 TLC plates. Flash column chromatography was
performed on Kanto Chemical Silica Gel 60N (spherical,
neutral 40–50 mm) with the solvents indicated.
All solvents and reagents were used as supplied with the
following exceptions. Tetrahydrofuran (THF) and ether

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1597
5:1/3:1) to give 14 (5.02 g, 53%) as a more polar product
and 15 (4.16 g, 44%) as a less polar product.
4.1.4. Conversion of 14 to 15. Diethyl azodicarboxylate in
toluene (40% solution, 14.5 ml, 34 mmol) was added
dropwise to a stirred solution of 14 (5.00 g, 17 mmol) in
dry THF (150 ml) containing triphenylphosphine (8.68 g,
34 mmol) and benzoic acid (4.15 g, 34 mmol) at 0 8C under
argon. The mixture was stirred for 3 h at room temperature.
Concentration of the mixture in vacuo afforded a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 13:1) to give the corresponding benzoate
(6.61 g, 98%) as a colorless oil. [a]2D0 C15.9 (c 1.06,
CHCl3); 1H NMR (500 MHz, CDCl3) d 0.09 (3H, s, Si-Me),
0.10 (3H, s, Si-Me), 0.90 (9H, s, Si-t-Bu), 1.37 (3H, s, C-
Me), 1.55 (3H, s, C-Me), 1.92–2.10 (3H, m, C4–H, C4–H,
C6–H), 2.24 (1H, dt, JZ5.1, 14.5 Hz, C6–H), 3.96 (1H, t,
JZ4.9 Hz, C2–H), 4.20 (1H, m, C3–H), 4.43 (1H, q, JZ
5.5 Hz, C1–H), 5.33 (1H, m, C5–H), 7.43 (2H, t, JZ7.8 Hz,
Ar-H), 7.55 (1H, t, JZ7.4 Hz, Ar-H), 8.05 (2H, d, JZ
7.1 Hz, Ar-H); 13C NMR (125 MHz, CDCl3) d K5.02,
K4.84, 17.9, 25.7 (4 carbons), 30.9, 33.95, 33.99, 67.5,
68.8, 69.6, 72.8, 128.3 (2 carbons), 129.6 (2 carbons), 130.5,
132.9, 165.8, 207.1; IR (neat) 520, 710, 780, 840, 920, 940,
970, 1010, 1030, 1070, 1110, 1220, 1280, 1320, 1370, 1380,
Compound 14. Colorless prism, mp 47–48 8C; [a]2D0 K41.7
(c 1.01, CHCl3); 1H NMR (500 MHz, CDCl3) d 0.10 (3H, s,
Si-Me), 0.11 (3H, s, Si-Me), 0.89 (9H, s, t-Bu), 1.34 (3H, s,
C-Me), 1.46 (3H, s, C-Me), 1.60 (1H, m, C4–H), 1.83 (1H,
m, C6–H), 2.00 (1H, m, C4–H), 2.20 (1H, m, C6–H), 2.26
(1H, d, JZ6.8 Hz, OH), 3.89–3.97 (2H, m, C2–H, C3–H),
4.02 (1H, br, C5–H), 4.40 (1H, dd, JZ4.8, 9.8 Hz, C1–H);
13C NMR (125 MHz, CDCl3) d K4.81, K4.72, 18.0, 25.8
(3 carbons), 25.9, 28.1, 35.5, 37.7, 65.1, 71.1, 72.7, 78.87,
108.5; IR (KBr) 510, 550, 630, 660, 690, 780, 840, 870, 920,
940, 960, 1020, 1040, 1060, 1120, 1190, 1220, 1240, 1260,
1370, 1380, 1460, 2860, 2890, 2930, 2990, 3420 cmK1
;
CIMS (m/z) 303 [(MCH)C]; HREIMS (m/z) calcd for
C14H27O4Si [(MKMe)C]: 287.1679, found 287.1682.
Compound 15. Colorless oil. [a]2D0 K33.7 (c 1.02, CHCl3);
1H NMR (500 MHz, CDCl3) d 0.08 (3H, s, Si-Me), 0.10
(3H, s, Si-Me), 0.88 (9H, s, t-Bu), 1.35 (3H, s, C-Me), 1.52
(3H, s, C-Me), 1.73 (1H, m, C4–H), 1.90 (1H, ddd, JZ3.9,
6.3, 13.7 Hz, C4–H), 2.04 (2H, t, JZ4.4 Hz, C6–H), 2.27
(1H, d, JZ8.2 Hz, OH), 3.90 (1H, t, JZ5.2 Hz, C2–H), 4.04
(1H, dd, br, JZ7.7, 10.7 Hz, C5–H), 4.09 (1H, m, C3–H),
4.41 (1H, dd, JZ4.6, 9.7 Hz, C1–H); 13C NMR (125 MHz,
CDCl3) d K4.81, K4.72, 18.0, 25.7, 25.8 (3 carbons), 28.2,
33.8, 37.9, 65.3, 68.7, 74.1, 78.9, 108.6; IR (neat) 520,
660, 780, 840, 910, 940, 960, 1000, 1050, 1070, 1120, 1150,
1220, 1250, 1380, 1460, 2860, 2890, 2930, 2960,
2990, 3440 cmK1; HREIMS (m/z) calcd for C14H27O4Si
[(MKMe)C]: 287.1679, found 287.1680.
1450, 1540, 1600, 1720, 1780, 2860, 2890, 2930 cmK1
;
HREIMS (m/z) calcd for C21H31O5Si [(MKMe)C]:
391.1941, found 391.1910.
2.0 M Potassium hydroxide solution (22.4 ml, 45 mmol)
was added dropwise to a stirred solution of the above
benzoate (6.50 g, 16 mmol) in methanol (280 ml) at 0 8C,
and stirring was continued for 3 h at room temperature.
The mixture was concentrated in vacuo to give a residue,
which was diluted with ethyl acetate (800 ml). The organic
layer was washed with brine (2!300 ml) and then dried
over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 3:1) to give 15
4.1.3. (1R,2R,3R,5R)-5-Acetoxy-3-tert-butyldimethyl-
siloxy-1,2-(O-isopropylidenedioxy)cyclohexane (16).
Acetic anhydride (0.1 ml, 1.1 mmol) was added to a stirred
solution of 14 (27 mg, 89 mmol) in pyridine (1.0 ml)
containing 4-dimethylaminopyridine (1.0 mg, 8 mmol) at
0 8C, and stirring was continued for 3 h at room
temperature. The reaction was quenched with saturated
aqueous sodium hydrogen carbonate (1 ml) at 0 8C, and the
mixture was diluted with ether (30 ml). The organic layer
was successively washed with 3% aqueous hydrochloric
acid (2!15 ml), saturated aqueous sodium hydrogen
carbonate (2!15 ml), and brine (2!10 ml), then dried
over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 7:1) to give 16
(30 mg, 98%) as a colorless oil. [a]2D0 K29.6 (c 1.01,
CHCl3); 1H NMR (500 MHz, CDCl3) d 0.07 (3H, s, Si-Me),
0.09 (3H, s, Si-Me), 0.89 (9H, s, Si-t-Bu), 1.34 (3H, s, C-
Me), 1.45 (1H, m, C4–H), 1.46 (3H, s, C-Me), 1.82 (1H, m,
C6–H), 2.03 (3H, s, Ac), 2.12 (1H, m, C4–H), 2.35 (1H, m,
C6–H), 3.80 (1H, m, C3–H), 3.87 (1H, t, JZ5.9 Hz, C2–H),
4.39 (1H, m, C1–H), 5.04 (1H, m, C5–H); 13C NMR
(125 MHz, CDCl3) d K4.85, K4.86, 18.0, 21.3, 25.4, 25.7
(3 carbons), 27.8, 31.2, 36.1, 66.8, 70.6, 73.0, 79.4, 108.5,
170.4; IR (neat) 410, 510, 610, 660, 700, 780, 840, 870, 900,
920, 940, 990, 1060, 1120, 1150, 1220, 1240, 1370, 1460,
1740, 2860, 2890, 2930, 2960, 2990 cmK1; HREIMS (m/z)
calcd for C16H29O5Si [(MKMe)C]: 329.1784, found
329.1796.
1
(4.82 g, quant.) as a colorless oil. The IR, H NMR, and
mass spectra of this material were identical with those
recorded for preparation of 15 (see, Section 4.1.2).
4.1.5. (3R,4R,5R)-5-tert-Butyldimethylsiloxy-3,4-O-iso-
propylidenedioxy-1-cyclohexene (17). Diethyl azodicar-
boxylate in toluene (40% solution, 21.6 ml, 50 mmol)
was added dropwise to a stirred solution of 15 (5.00 g,
17 mmol) in dry THF (150 ml) containing triphenyl-
phosphine (13.1 g, 51 mmol) at room temperature. After
3 h, the mixture was concentrated in vacuo to afford a
residue, which was purified by column chromatography
(hexane/ethyl acetate, 13:1) to give 17 (3.15 g, 67%) as a
colorless oil. [a]D20 K87.1 (c 1.05, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.07 (3H, s, Si-Me), 0.10 (3H, s,
Si-Me), 0.89 (9H, s, Si-t-Bu), 1.38 (3H, s, C-Me), 1.46
(3H, s, C-Me), 2.01 (1H, m, C6–H), 2.28 (1H, m, C6–H),
3.83 (1H, m, C5–H), 3.98 (1H, t, JZ6.8 Hz, C4–H), 4.60
(1H, d, JZ6.2 Hz, C3–H), 5.80 (2H, m, C1–H, C2–H);
13C NMR (125 MHz, CDCl3) d K4.8, K4.5, 18.1, 25.8
(3 carbons), 26.1, 28.3, 31.9, 69.6, 72.8, 78.7, 108.6,
124.6, 128.5; IR (neat) 670, 780, 840, 910, 1010, 1060,
1120, 1220, 1250, 1380, 1460, 1690, 1730, 2860,
2930, 2960 cmK1; HREIMS (m/z) calcd for C14H25O3Si
[(MKMe)C]: 269.1573, found 269.1570.

1598
T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
4.1.6. (1S,2S,3R,4R,5R)-5-tert-Butyldimethylsiloxy-
1,2-epoxy-3,4-(O-isopropylidenedioxy)cyclohexane (18).
3-Chloroperoxybenzoic acid (mCPBA) (7.53 g, 45 mmol)
was added in small portions to a stirred solution of 17
(4.95 g, 17 mmol) in dry dichloromethane (180 ml) contain-
ing sodium hydrogen carbonate (7.53 g, 45 mmol) at 0 8C,
and stirring was continued for 24 h at room temperature.
The reaction was diluted with ethyl acetate (400 ml). The
organic layer was washed with saturated aqueous sodium
hydrogen carbonate (2!200 ml) and brine (2!200 ml),
then dried over Na2SO4. Concentration of the solvent in
vacuo affoded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 13:1) to give 18
(4.81 g, 92%) as a colorless oil. [a]2D0 K29.1 (c 1.04,
CHCl3); 1H NMR (500 MHz, CDCl3) d 0.06 (3H, s, Si-Me),
0.07 (3H, s, Si-Me), 0.88 (9H, s, Si-t-Bu), 1.38 (3H, s, C-
Me), 1.46 (3H, s, C-Me), 1.90 (1H, ddd, JZ1.6, 6.1,
15.6 Hz, C6–H), 2.18 (1H, ddd, JZ4.0, 5.1, 15.4 Hz,
C6–H), 3.14 (1H, d, JZ3.6 Hz, C2–H), 3.23 (1H, s, C1–H),
3.87 (1H, dd, JZ5.8, 11.2 Hz, C5–H), 3.94 (1H, m, C4–H),
4.53 (1H, d, JZ5.6 Hz, C3–H); 13C NMR (125 MHz,
CDCl3) d K4.77, K4.75, 18.0, 25.7 (3 carbons), 26.0, 28.0,
29.4, 51.3, 51.7, 66.3, 71.8, 76.8, 109.2; IR (neat) 510, 710,
780, 840, 870, 910, 940, 1000, 1110, 1220, 1250, 1380,
1470, 2860, 2890, 2930, 2990 cmK1; HREIMS (m/z) calcd
for C14H25O4Si [(MKMe)C]: 285.1522, found 285.1508.
4.1.8. (4R,5R,6S)-4-tert-Butyldimethylsiloxy-5,6-O-iso-
propylidenedioxy-2-cyclohexen-1-one (10). Dess–Martin
periodinane (14.5 g, 34 mmol) was added in small portions
to a stirred solution of 19 (5.15 g, 17 mmol) in dry
dichloromethane (200 ml) at room temperature. After 2 h,
the mixture was diluted with ethyl acetate (500 ml). The
organic layer was washed successively with 20% aqueous
sodium thiosulfate (2!200 ml), saturated aqueous sodium
hydrogen carbonate (2!200 ml), and brine (2!200 ml),
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 7:1) to give 10
(4.86 g, 95%) as a white solid. Recrystallization from
hexane/dichloromethane (5:1) afforded colorless prisms, mp
55–56 8C; [a]2D0 K84.7 (c 1.02, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.14 (3H, s, Si-Me), 0.17 (3H, s, Si-
Me), 0.92 (9H, s, Si-t-Bu), 1.40 (3H, s, C-Me), 1.42 (3H, s,
C-Me), 4.41 (1H, m, C5–H), 4.44 (1H, d, JZ5.9 Hz, C6–H),
4.54 (1H, m, C4–H), 6.08 (1H, d, JZ10.3 Hz, C2–H), 6.76
(1H, ddd, JZ1.0, 3.8, 10.3 Hz, C3–H); 13C NMR
(125 MHz, CDCl3) d K4.74 (Si-Me), K4.73 (Si-Me),
18.1 (C-Me3), 25.7 (3 carbons, C-Me3), 25.9 (Me of
O-isopropylidene), 27.4 (Me of O-isopropylidene), 67.1
(C4), 74.4 (C5), 79.6 (C6), 110.2 (C-Me2 of
O-isopropylidene), 127.9 (C2), 148.5 (C3), 194.5 (C1); IR
(KBr) 470, 520, 630, 670, 730, 780, 840, 890, 940,
980, 1010, 1080, 1170, 1250, 1330, 1380, 1460, 1630,
1700, 2710, 2740, 2860, 2900, 2930, 2990, 3040, 3370,
3550 cmK1; EIMS (m/z) 298 (MC), 283 [(MKMe)C], 241
[(MKt-Bu)C]. Anal. Calcd for C15H26O4Si: C, 60.37; H,
8.78. Found C, 60.03; H, 8.56.
4.1.7.
(1S,4R,5R,6R)-4-tert-Butyldimethylsiloxy-1-
hydroxy-5,6-O-isopropylidenedioxy-2-cyclohexene (19).
Sodium borohydride (663 mg, 18 mmol) was added in
small portions to a stirred suspension of diphenyl
diselenide (2.74 g, 8.8 mmol) in dry ethanol (30 ml) at
0 8C under argon. After 30 min, a solution of 18 (4.80 g,
16 mmol) in dry ethanol (30 ml) was added dropwise to
the mixture at room temperature. The mixture was heated
at reflux for 1 h. After cooling, the mixture was diluted
with dry THF (24 ml). Hydrogen peroxide in water (30%
solution, 19.5 ml, 0.17 mol) was added dropwise to the
mixture at 0 8C. The resulting mixture was further stirred
for 5 min at 0 8C and slowly heated at reflux for 1 h.
After cooling, the mixture was diluted with ether
(300 ml). The organic layer was washed with saturated
aqueous sodium hydrogen carbonate (2!150 ml) and
brine (2!100 ml), then dried over Na2SO4. Concen-
tration of the solvent in vacuo gave a residue, which was
purified by column chromatography (hexane/ethyl
acetate, 3:1) to give 19 (3.74 g, 78%) as a colorless
oil. [a]2D0 K42.4 (c 1.03, CHCl3); 1H NMR (500 MHz,
CDCl3) d 0.11 (3H, s, Si-Me), 0.13 (3H, s, Si-Me), 0.90
(9H, s, Si-t-Bu), 1.34 (3H, s, C-Me), 1.40 (3H, s, C-Me),
2.90 (1H, d, JZ8.3 Hz, OH), 4.12 (1H, m, C1–H), 4.21
(1H, t, JZ3.7 Hz, C4–H), 4.29 (1H, dd, JZ4.1, 7.5 Hz,
C5–H), 4.33 (1H, dd, JZ4.1, 7.5 Hz, C6–H), 5.95 (1H,
dd, JZ4.2, 9.8 Hz, C3–H), 6.07 (1H, dd, JZ4.2, 9.8 Hz,
C2–H); 13C NMR (125 MHz, CDCl3) d K4.81, K4.75,
18.0, 24.6, 25.8 (3 carbons), 26.6, 67.9, 68.7, 78.8, 79.0,
108.7, 132.3, 132.3; IR (neat) 410, 480, 520, 640, 660,
690, 780, 840, 890, 940, 960, 990, 1010, 1060, 1120,
1160, 1210, 1250, 1380, 1460, 1640, 2860, 2900, 2930,
2960, 2990, 3050, 3450 cmK1; HREIMS (m/z) calcd for
C14H25O4Si [(MKMe)C]: 285.1522, found 285.1534.
4.1.9. (1S,5R,6S,10R,20R,30R,40S)-5,20-Bis(tert-butyl-
dimethylsiloxy)-1,6:30,40-bis(O-isopropylidenedioxy)bi-
cyclohexyl-3-ene-2,50-dione (20) and (4R,5S,6S)-6-
benzoyl-4-tert-butyldimethylsiloxy-5,6-O-isopropylide-
nedioxy-2-cyclohexen-1-one (22). Lithium bis(trimethylsi-
lyl)amide in THF (1.0 M solution, 1.7 ml, 1.7 mmol) was
added dropwise to a stirred solution of 10 (50 mg,
0.17 mmol) and benzaldehyde (8) (82 ml, 0.77 mmol) in
dry THF (4 ml) at K78 8C under argon, and the stirring was
continued for 30 min at the same temperature. The reaction
was quenched with saturated aqueous ammonium chloride
(1 ml) at 0 8C, and the mixture was diluted with ether
(50 ml). The organic layer was washed successively with
saturated aqueous ammonium chloride (2!20 ml), satu-
rated aqueous sodium hydrogen carbonate (2!20 ml), and
brine (2!20 ml), then dried over Na2SO4. Concentration of
the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/ethylacetate, 7:1) to
give 20 (19 mg, 38%) as a white amorphous solid and 21
(7.4 mg, 12%) as colorless oil. Since compound 21 was
unstable, this was immediately subjected to the following
oxidation reaction.
Compound 21 (7.4 mg, 18 mmol) was treated with Dess–
Martin periodinane (23.0 mg, 54 mmol) in dichloromethane
(0.5 ml) at room temperature for 1 h. The reaction mixture
was diluted with ethyl acetate (30 ml). The organic layer
was washed successively with 20% aqueous sodium
thiosulfate (2!10 ml), saturated aqueous sodium hydrogen
carbonate (2!10 ml), and brine (2!10 ml), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1599
a residue, which was purified by column chromatography
(hexane/ethyl acetate, 7:1) to give 22 (5.7 mg, 78%) as a
colorless viscous oil.
JZ8.4 Hz, C9–H), 2.90 (1H, ddd, JZ3.3, 5.6, 10.2 Hz,
C4a–H), 3.08 (1H, s, C1–H), 3.11 (1H, s, C4–H), 3.18 (1H,
dd, JZ3.8, 10.2 Hz, C8a–H), 3.99 (1H, t, JZ6.2 Hz,
C5–H), 4.12 (1H, d, JZ8.4 Hz, C7–H), 4.22 (1H, dd, JZ
7.0, 8.3 Hz, C6–H), 6.12 (1H, dd, JZ3.0, 5.6 Hz, C2–H),
6.20 (1H, dd, JZ3.0, 5.4 Hz, C3–H); 13C NMR (125 MHz,
CDCl3) d K4.93, K4.53, 18.0, 24.0, 25.8 (3 carbons), 26.5,
45.2, 45.7, 46.6, 49.6, 51.6, 71.6, 78.1, 79.7, 109.9, 133.1,
137.0, 208.7; IR (KBr) 560, 680, 730, 780, 840, 850, 900,
940, 970, 1010, 1040, 1080, 1110, 1160, 1210, 1260, 1380,
1460, 1720, 2860, 2900, 2930, 2960 cmK1; EIMS (m/z)
349 [(MKMe)C], 307 [(MKt-Bu)C], 249 [(MKTBS)C];
CIMS (m/z) 365 [(MCH)C]; HREIMS (m/z) calcd for
C19H29O4Si [(MKMe)C]: 349.1835, found 349.1825.
Compound 20. [a]D20 K30.0 (c 1.10, CHCl3); 10 H NMR
(500 MHz, CDCl3) d 0.10 (3H, s, Si-Me of C6 –OTBS),
0.15 (3H, s, Si-Me of C5–OTBS), 0.17 (3H, s, Si-Me of
C5–OTBS), 0.22 (3H, s, Si-Me of C60–OTBS), 0.84 (9H, s,
t-Bu of C60–OTBS), 0.92 (9H, s, t-Bu of C5–OTBS), 1.27
(3H, s, Me of O-isopropylidene), 1.30 (3H, s, Me of
O-isopropylidene), 1.35 (3H, s, Me of O-isopropylidene),
1.45 (3H, s, Me of O-isopropylidene), 2.58 (1H, dd, JZ7.0,
16.8 Hz, C20–H), 2.70 (1H, dd, JZ10.5, 17.8 Hz, C20–H),
2.908 (1H, dd, JZ7.1, 10.3 Hz, C10–H), 4.05 (1H, br s,
C6 –H), 4.10 (1H, t, JZ1.7 Hz, C6–H), 4.26 (2H, br, C40–
H, C50–H), 4.61 (1H, dd, JZ1.0, 4.3 Hz, C5–H), 6.01 (1H,
d, JZ10.2 Hz, C3–H) 6.58 (1H, br, C4–H); 13C NMR
(125 MHz, CD2Cl2) d K4.89, K4.80, K4.44, K4.30, 18.3,
18.4, 24.5, 25.9 (6 carbons), 26.5, 26.6, 27.1 (2 carbons),
30.1, 65.9, 78.2 (2 carbons), 79.3, 80.2, 83.5, 109.2, 111.9,
127.7, 143.5, 198.8, 204.5; IR (neat) 520, 670, 780, 810,
840, 940, 960, 980, 1010, 1040, 1070, 1100, 1130, 1180,
1210, 1230, 1260, 1380, 1470, 1700, 1730, 2860, 2930,
2950, 2990 cmK1; HREIMS (m/z) calcd for C29H49O8Si2
[(MKMe)C], 581.2966, found 581.2949.
4.1.11. (1R,4S,4aR,5R,6S,7S,8aS)-5-Trihydroxy-6,7-O-
isopropylidenedioxy-1,4,4a,5,6,7,8,8a-octahydro-endo-
1,4-methanonaphthalen-8-one (28). Tetrabutylammonium
fluoride in THF (1.0 M solution, 15.0 ml, 15 mmol) was
added to a stirred solution of 27 (3.51 g, 9.6 mmol) in dry
THF (100 ml) at 0 8C, and stirring was continued for 2 h at
room temperature. The mixture was diluted with ether
(400 ml). The organic layer was successively washed with
saturated aqueous ammonium chloride (2!150 ml), satu-
rated aqueous sodium hydrogen carbonate (2!150 ml), and
brine (2!150 ml), then dried over Na2SO4. Concentration
of the solvent in vacuo afforded a residue, which was
purified by column chromatography (hexane/ethyl acetate,
5:3) to give 24 (1.81 g, 75%) as a white solid. Recrystalliza-
tion from hexane/dichloromethane (10:1) afforded colorless
needles, mp 137–138 8C; [a]2D0 C112.9 (c 1.00, CHCl3); 1H
NMR (500 MHz, CDCl3) d 1.34 (3H, s, C-Me), 1.42 (1H, d,
JZ8.4 Hz, C9–H), 1.53 (3H, s, C-Me), 1.58 (1H, d, JZ
8.4 Hz, C9–H), 2.16 (1H, s, OH), 3.08–3.16 (3H, m, C1–H,
C4–H, C5–H), 3.38 (1H, dd, JZ3.3, 10.5 Hz, C8a–H), 4.15
(1H, t, JZ4.1 Hz, C4a–H), 4.20 (1H, d, JZ8.0 Hz, C7–H),
4.43 (1H, dd, JZ5.9, 8.0 Hz, C6–H), 6.25 (1H, dd, JZ2.6,
5.5 Hz, C3–H), 6.37 (1H, dd, JZ3.0, 5.5 Hz, C2–H); 13C
NMR (125 MHz, CDCl3) d 23.9, 26.4, 44.6 (2 carbons),
45.3, 48.4, 51.7, 70.2, 78.1, 79.7, 111.0, 134.9, 137.4, 208.6;
IR (KBr) 550, 740, 860, 890, 1040, 1060, 1160, 1210, 1260,
1380, 1630, 1710, 2940, 2980, 3440 cmK1; EIMS (m/z) 250
(MC), 235 [(MKMe)C]. Anal. Calcd for C14H18O4: C,
67.18; H, 7.25. Found: C, 67.35, H, 7.24.
Compound 22. [a]D20 K3.27 (c 1.00, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.14 (3H, s, Si-Me), 0.15 (3H, s, Si-
Me), 0.92 (9H, s, t-Bu), 1.27 (3H, s, C-Me), 1.46 (3H, s, C-
Me), 4.58 (1H, dt, JZ1.6, 2.2 Hz, C4–H), 4.79 (1H, dd, JZ
1.2, 3.0 Hz, C5–H), 6.13 (1H, dd, JZ1.6, 10.3 Hz, C2–H),
6.79 (1H, ddd, JZ1.2, 3.4, 10.3 Hz, C3–H), 7.42 (2H, t, JZ
7.8 Hz, Ph-H), 7.55 (1H, d, JZ7.8 Hz, Ph-H), 8.22 (2H, d,
JZ7.3 Hz, Ph-H); 13C NMR (125 MHz, CDCl3) d K4.82,
K4.72, 18.1, 25.7 (3 carbons), 26.3, 27.4, 68.1, 82.8, 89.7,
111.3, 127.1, 128.1 (2 carbons), 130.8 (2 carbons), 133.3,
134.9, 148.8, 192.8, 196.9; IR (neat) 690, 780, 840, 870,
900, 1050, 1100, 1180, 1260, 1380, 1450, 1460, 1580, 1600,
1680, 1700, 2860, 2890, 2930, 2960, 2990 cmK1; HREIMS
(m/z) calcd for C22H30O5Si (MC): 402.1863, found
402.1835.
4.1.10. (1R,4S,4aR,5R,6S,7S,8aS)-5-tert-Butyldimethylsil-
oxy-6,7-O-isopropylidenedioxy-1,4,4a,5,6,7,8,8a-octahy-
dro-endo-1,4-methanonaphthalen-8-one
(27).
Diethylaluminum chloride in hexane (1.0 M solution,
2.68 ml, 0.27 mmol) was added dropwise to a stirred
solution of 10 (4.00 g, 13 mmol) and cyclopentadiene
(11.1 ml, 0.13 mol) in dry dichloromethane (140 ml) at
K78 8C under argon. The mixture was gradually warmed up
to 0 8C over 1 h, and stirring was continued for 1 h at 0 8C.
The mixture was diluted with ether (400 ml). The organic
layer was washed with saturated aqueous sodium hydrogen
carbonate (2!200 ml) and brine (2!200 ml), then dried
over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 6:1) to give 27
(4.74 g, 97%) as a white solid. Recrystallization from
hexane/dichloromethane (10:1) afforded colorless prisms,
mp 92–93 8C; [a]D20 C46.7 (c 1.01, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.08 (3H, s, Si-Me), 0.09 (3H, s, Si-
Me), 0.89 (9H, s, Si-t-Bu), 1.30 (3H, s, C-Me), 1.37 (1H, d,
JZ8.4 Hz, C9–H), 1.47 (3H, s, C-Me), 1.54 (1H, d,
4.1.12.
(1S,2S,3S,4R,4aR,5R,6S,7S,8aR)-2-Bromo-
3,5-epoxy-6,7-(O-isopropylidenedioxy)perhydro-endo-
1,4-methanonaphthalen-8-one (25). N-Bromosuccinimide
(2.78 g, 16 mmol) was added in small portions to a stirred
solution of 28 (3.02 g, 12 mmol) in dry dichloromethane
(180 ml) at 0 8C, and stirring was continued for 1 h at room
temperature. The mixture was diluted with ether (400 ml).
The organic layer was washed successively with 20%
aqueous sodium thiosulfate (2!150 ml), saturated aqueous
sodium hydrogen carbonate (2!150 ml), and brine (2!
150 ml), then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/ethyl acetate, 4:1) to give
25 (3.41 g, 86%) as a white solid. Recrystallization from
hexane/ether (5:1) afforded pale yellow prisms, mp 121–
122 8C; [a]2D0 C65.9 (c 1.00, CHCl3); 1H NMR (500 MHz,
CDCl3) d 1.33 (3H, s, C-Me), 1.52 (3H, s, C-Me), 1.67
(1H, d, JZ11.2 Hz, C9–H), 1.22 (1H, d, JZ11.2 Hz,

1600
T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
C9–H), 2.82 (1H, br, C1–H), 2.97 (1H, br, C4–H), 3.00–
3.10 (2H, m, C4a–H, C8a–H), 3.82 (1H, d, JZ1.2 Hz,
C2–H), 3.88 (1H, t, JZ1.9 Hz, C5–H), 4.28 (1H, d, JZ
6.3 Hz, C7–H), 4.44 (1H, dd, JZ0.8, 5.3 Hz, C3–H), 4.54
(1H, dd, JZ1.7, 6.3 Hz, C6–H); 13C NMR (125 MHz,
CDCl3) d 24.7, 26.6, 33.7, 41.4, 42.7, 46.1, 47.5, 55.0, 77.5,
77.7, 78.1, 87.3, 111.2, 207.0; IR (KBr) 540, 710, 750, 770,
810, 840, 860, 890, 940, 970, 1060, 1090, 1160, 1210, 1270,
(hexane/ethyl acetate, 2:1/1:1) to give 23 (29.3 mg, 98%)
as a hardly separable epimeric mixture (6:1 by 500 MHz 1H
NMR). In order to obtain analytical samples, a small amount
of the epimeric mixture 23 was further subjected to column
chromatography (hexane/ethyl acetate, 2:1/1:1) to pro-
vide pure samples of 23a (major, more polar) and 23b
(minor, less polar).
1310, 1380, 1460, 1720, 1790, 2890, 2940, 2990 cmK1
;
Compound 23a. Colorless prisms; mp 181–182 8C; [a]D20
K68.9 (c 1.17, CHCl3); 1H NMR (500 MHz, CDCl3) d 0.98
(3H, s, C-Me), 1.38 (3H, s, C-Me), 1.61 (1H, d, JZ5.2 Hz,
OH), 1.78 (1H, d, JZ11.5 Hz, C11–H), 1.84 (1H, d, JZ
11.5 Hz, C11–H), 2.30 (1H, d, JZ5.2 Hz), 2.45 (1H, s), 2.90
(1H, t, JZ2.3 Hz), 3.13 (1H, d, JZ4.1 Hz), 4.44 (1H, d, JZ
3.0 Hz), 4.51 (1H, t, JZ2.3 Hz), 4.52 (1H, t, JZ2.8 Hz),
5.05 (1H, d, JZ8.5 Hz), 7.28–7.36 (3H, m, Ph), 7.42–7.46
(2H, m, Ph); 13C NMR (125 MHz, CDCl3) d 20.9, 26.2,
28.0, 30.3, 30.4, 32.4, 41.1, 46.6, 76.4, 77.7, 79.6, 83.2,
88.1, 110.1, 127.8 (2 carbons), 128.4, 129.2 (2 carbons),
138.0, 205.6; IR (KBr) 510, 600, 700, 730, 830, 880, 920,
1020, 1060, 1110, 1170, 1250, 1290, 1380, 1450, 1720,
2940, 2990, 3380 cmK1; EIMS (m/z) 337 [(MKOH)C];
CIMS (m/z) 355 [(MCH)C]. Anal. Calcd for C21H22O6: C,
71.17; H, 6.26. Found: C, 71.24; H 6.35.
EIMS (m/z) 330 [(MC2)C, 81Br], 328 (MC, 79Br), 315
[(MKMeC2)C, 81Br], 313 [(MKMe)C, 79Br]. Anal. calcd
for C14H17BrO4: C, 51.08; H, 5.21; Br, 24.27. Found: C,
51.33; H, 5.23; Br, 24.50.
4.1.13. (1R,2S,4S,5S,6R,7R,8R,9S,10S)-6,9-Epoxy-4,5-
(O-isopropylidenedioxy)tetracyclo[6.2.1.02,7.02,10]unde-
can-3-one (29). Lithium bis(trimethylsilyl)amide in THF
(1.0 M solution, 67 ml, 67 mmol) was added dropwise to a
stirred solution of 25 (20 mg, 61 mmol) in dry THF (1.5 ml)
at K78 8C under argon, and the stirring was continued for
30 min at the same temperature. The reaction was quenched
with saturated aqueous ammonium chloride (1 ml) at
K78 8C, and the mixture was diluted with ether (40 ml).
The organic layer was washed successively with saturated
aqueous ammonium chloride (2!15 ml), saturated aqueous
sodium hydrogen carbonate (2!15 ml), and brine (2!
15 ml), then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/ethyl acetate, 2:1) to give
29 (15 mg, 98%) as a white solid. Recrystallization from
hexane/dichloromethane (10:1) afforded colorless prisms,
mp 77–78 8C; [a]D20 K61.6 (c 1.05, CHCl3); 1H NMR
(500 MHz, CDCl3) d 1.39 (3H, s, C-Me); 1.45 (3H, s, C-
Me); 1.67 (1H, dd, JZ1.3, 5.0 Hz, C10–H); 1.80 (1H, d, JZ
11.4 Hz, C11–H); 1.86 (1H, d, JZ11.4 Hz, C11–H); 2.42
(1H, d, JZ4.3 Hz, C1–H); 2.46 (1H, s, C8–H); 2.87 (1H, t,
JZ2.4 Hz, C7–H); 4.40–4.45 (3H, m, C4–H, C6–H, C9–H);
4.66 (1H, dd, JZ1.3, 5.7 Hz, C5–H); 13C NMR (125 MHz,
CDCl3) d 21.5, 25.0, 27.2, 30.4, 32.5, 34.3, 41.7, 44.7, 77.6,
77.9, 79.4, 82.5, 110.1, 201.7; IR (KBr) 520, 580, 630, 830,
860, 880, 920, 940, 960, 990, 1020, 1040, 1070, 1160, 1210,
1270, 1300, 1330, 1380, 1700, 2880, 2900, 2940,
2990 cmK1; EIMS (m/z) 248 (MC), 233 [(MKMe)C],
190 [(MKMe2CO)C]. Anal. Calcd for C14H16O4: C, 67.73;
H, 6.50. Found: C, 67.51; H, 6.57.
Compound 23b. Colorless viscous oil. [a]2D0 K85.2 (c 1.20,
CHCl3); 1H NMR (500 MHz, CDCl3) d 0.91 (3H, s, C-Me),
1.38 (3H, s, C-Me), 1.78 (1H, d, JZ11.5 Hz, C11–H), 1.84
(1H, d, JZ11.5 Hz, C11–H), 1.92 (1H, dd, JZ1.5, 5.1 Hz,
OH), 2.41 (1H, d, JZ5.1 Hz), 2.46 (1H, s), 2.89 (1H, t, JZ
2.3 Hz), 3.23 (1H, d, JZ8.6 Hz), 4.51 (2H, m), 4.69 (1H, d,
JZ2.7 Hz), 5.06 (1H, d, JZ8.5 Hz), 7.27–7.31 (1H, m, Ph),
7.34 (2H, t, JZ7.4 Hz, Ph), 7.44 (2H, d, JZ7.2 Hz, Ph); 13C
NMR (125 MHz, CDCl3) d 22.4, 26.5, 28.5, 30.3, 33.3,
33.3, 41.0, 45.2, 75.3, 77.0, 78.6, 83.3, 86.9, 110.5, 127.8 (2
carbons), 128.1, 128.5 (2 carbons), 139.2, 204.2; IR (neat)
510, 590, 710, 730, 830, 880, 920, 1060, 1170, 1240, 1290,
1380, 1450, 1700, 2940, 2990, 3470 cmK1; EIMS (m/z) 337
[(MKOH)C], 248 [(MKPhCHO)C] CIMS (m/z) 355
[(MCH)C]; HREIMS (m/z) calcd for C14H16O4 [(MK
PhCHO)C]: 248.1049, found 248.1057.
4.1.15. One-pot procedure for the preparation of 23 from
25. Lithium bis(trimethylsilyl)amide in THF (1.0 M
solution, 1.43 ml, 1.4 mmol) was added dropwise to a
stirred solution of 25 (213 mg, 0.65 mmol) in dry THF
(8 ml) at K78 8C under argon. After 30 min, a solution of
benzaldehyde (8) (0.20 ml, 2.0 mmol) in dry THF (1 ml)
was added slowly to the mixture at K78 8C, and the stirring
was continued for 1 h at the same temperature. The reaction
was quenched with saturated aqueous ammonium chloride
(2 ml) at 0 8C, and the mixture was diluted with ether
(50 ml). The organic layer was washed successively with
saturated aqueous ammonium chloride (2!20 ml), satu-
rated aqueous sodium hydrogen carbonate (2!20 ml), and
brine (2!20 ml), then dried over Na2SO4. Concentration of
the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/ethyl acetate, 2:1/
1:1) to give 23 (225 mg, 98%) as an epimeric mixture (6:1
by 500 MHz 1H NMR). The IR, 1H NMR, and mass spectra
of this material were identical with those recorded for the
preparation of 23 (see, Section 4.1.14).
4.1.14. (1R,2S,4S,5S,6R,7R,8R,9S,10S)-6,9-Epoxy-4-
[hydroxy(phenyl)methy]-4,5-(O-isopropylidenedioxy)-
tetracyclo[6.2.1.02,7.02,10]undecan-3-one (23). Lithium
bis(trimethylsilyl)amide in THF (1.0 M solution, 94 ml,
94 mmol) was added dropwise to a stirred solution of 29
(21.0 mg, 85 mmol) in dry THF (1.0 ml) at K78 8C under
argon. After 30 min, a solution of benzaldehyde (8) (18 ml,
0.17 mmol) in dry THF (0.5 ml) was added slowly at
K78 8C, and the stirring was continued for 1 h at the same
temperature. The reaction was quenched with saturated
aqueous ammonium chloride (1 ml) at 0 8C, and the mixture
was diluted with ether (15 ml). The organic layer was
washed successively with saturated aqueous ammonium
chloride (2!7 ml), saturated aqueous sodium hydrogen
carbonate (2!7 ml), and brine (2!7 ml), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1601
4.1.16. [(1R,2S,4S,5S,6R,7R,8R,9S,10S)-6,9-Epoxy-
4,5-(O-isopropylidenedioxy)tetracyclo[6.2.1.02,7.02,10]un-
decan-3-one-4-yl](phenyl)methyl O-phenyl carbonothio-
ate (30). Phenyl thionochloroformate (0.18 ml, 1.3 mmol)
was added to a stirred solution of 23 (6:1 epimeric mixture)
(230 mg, 0.65 mmol) in dry acetonitrile (10 ml) containing
4-dimethylaminopyridine (DMAP) (316 mg, 2.6 mmol) at
room temperature. After 12 h, the mixture was diluted with
diethyl ether (100 ml). The organic layer was successively
washed with 3% aqueous hydrochloric acid (2!50 ml),
saturated aqueous sodium hydrogen carbonate (2!50 ml),
and brine (2!50 ml), then dried over Na2SO4. Concen-
tration of the solvent in vacuo afforded a residue, which was
purified by column chromatography (hexane/ethyl acetate,
5:2) to give 30 (292 mg, 92%) as a hardly separable
epimeric mixture (6:1 by 500 MHz 1H NMR), as a colorless
oil. In order to obtain analytical samples, a small amount of
the epimeric mixture 30 was further subjected to column
chromatography (hexane/ethyl acetate, 4:1/3:1) to pro-
vide pure samples of 30a (major, more polar) and 30b
(minor, less polar).
argon. The mixture was heated at reflux for 2 h. After
cooling, the mixture was concentrated in vacuo to afford a
residue, which was purified by column chromatography
(hexane/ethyl acetate, 1:0/3:1) to give 31 (116 mg, 79%)
as a white solid. Recrystallization from hexane/ether (5:1)
afforded colorless prisms, mp 107–108 8C; [a]2D0 K69.6 (c
0.97, CHCl3); 1H NMR (500 MHz, CDCl3) d 0.91 (3H, s, C-
Me), 1.36 (3H, s, C-Me), 1.67 (1H, dd, JZ1.6, 5.1 Hz, C10–
H), 1.80 (1H, d, JZ11.4 Hz, C11–H), 1.85 (1H, d, JZ
11.4 Hz, C11–H), 2.33 (1H, d, JZ4.9 Hz, C1–H), 2.46 (1H,
s, C8–H), 2.90 (1H, t, JZ2.3 Hz, C7–H), 2.99 (1H, d, JZ
13.7 Hz, CHaHbPh), 3.22 (1H, d, JZ13.7 Hz, CHaHbPh),
4.39 (1H, d, JZ3.0 Hz, C5–H), 4.54 (1H, t, JZ2.8 Hz,
C6–H), 4.57 (1H, t, JZ2.3 Hz, C9–H), 7.22–7.34 (5H, m,
Ph); 13C NMR (125 MHz, CDCl3) d 20.6, 26.3, 28.1, 30.3,
31.9, 31.9, 41.2, 43.3, 46.1, 76.8, 78.5, 83.2, 85.7, 109.2,
127.0, 127.9 (2 carbons), 131.9 (2 carbons), 135.2, 207.5; IR
(KBr) 510, 620, 700, 770, 830, 880, 920, 940, 990, 1030,
1060, 1080, 1100, 1120, 1140, 1170, 1240, 1300, 1330,
1380, 1450, 1490, 1710, 2870, 2930, 2990 cmK1; EIMS (m/
z) 338 (MC), 280 [(MKMe2CO)C], 247 [(MKPhCH2)C].
Anal. Calcd for C21H22O4: C, 74.54; H 6.55. Found: C,
74.65; H, 6.61.
Compound 30a. Colorless viscous oil. [a]2D0 K33.4 (c 1.05,
CHCl3); 1H NMR (500 MHz, CDCl3) d 1.09 (3H, s, C-Me),
1.44 (3H, s, C-Me), 1.68 (1H, br), 1.75 (1H, d, JZ11.5 Hz),
1.83 (1H, d, JZ11.5 Hz), 2.23 (1H, d, JZ5.2 Hz), 2.44 (1H,
s), 2.90 (1H, t, JZ2.4 Hz), 4.50 (1H, br), 4.53 (1H, t, JZ
2.7 Hz), 4.60 (1H, br d, JZ2.2 Hz), 6.70 (1H, s), 6.99–7.03
(2H, m), 7.22–7.27 (1H, m), 7.32–7.41 (5H, m), 7.51–7.55
(2H, m); 13C NMR (125 MHz, CDCl3) d 20.5, 26.2, 28.1,
30.1, 30.3, 32.2, 41.2, 46.9, 76.5, 80.0, 83.2, 86.2, 87.1,
110.8, 121.9 (2 carbons), 126.5, 128.0 (2 carbons), 129.2,
129.4 (2 carbons), 130.2 (2 carbons), 133.8, 153.5, 194.1,
202.2; IR (neat) 510, 690, 750, 850, 880, 940, 1030, 1070,
1120, 1200, 1270, 1380, 1460, 1490, 1590, 1710, 2940,
2990 cmK1; HREIMS (m/z) calcd for C28H26O6S (MC):
490.1450, found 490.1428.
4.1.18. (1S,2S,3S,4R,4aR,5R,6S,7S,8aR)-7-Benzyl-3,5-
epoxy-2-iodo-6,7-O-isopropylidenedioxy-1,2,3,4,4a,5,6,8a-
octahydro-endo-1,4-methanonaphthalen-8-one (32). Iodo-
trimethylsilane (0.10 ml, 0.70 mmol) was added dropwise to
a stirred solution of 31 (120 mg, 0.36 mmol) in carbon
tetrachloride (4 ml) at K20 8C under argon, and stirring was
continued for 3 h at K10 8C. The reaction was quenched
with 20% aqueous sodium thiosulfate (2 ml) at K10 8C, and
then the mixture was diluted with ether (40 ml). The organic
layer was washed successively with 20% aqueous sodium
thiosulfate (2!20 ml), saturated aqueous sodium hydrogen
carbonate (2!20 ml), and brine (2!20 ml), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography
(hexane/ethyl acetate, 4:1) to give 32 (147 mg, 89%) as a
colorless viscous oil. [a]2D0 C62.7 (c 0.96, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.89 (3H, s, C-Me), 1.32 (3H, s, C-
Me), 1.84 (1H, d, JZ11.3 Hz, C9–H), 2.24 (1H, d, JZ
11.3 Hz, C9–H), 2.88–2.97 (4H, m, C1–H, C4–H, C4a–H,
CHaHbPh), 3.07 (1H, dd, JZ4.9, 10.1 Hz, C8a–H), 3.35
(1H, d, JZ14.1 Hz, CHaHbPh), 3.61 (1H, d, JZ2.4 Hz,
C2–H), 4.25 (1H, t, JZ3.7 Hz, C5–H), 4.36 (1H, d, JZ
4.3 Hz, C6–H), 4.80 (1H, d, JZ5.4 Hz, C3–H), 7.22–7.32
(5H, m, Ph); 13C NMR (125 MHz, CDCl3) d 26.5, 28.3,
33.0, 36.5, 38.7, 39.7, 47.0, 47.7, 48.2, 75.7, 76.1, 82.1,
89.4, 110.3, 126.8, 127.9 (2 carbons), 132.0 (2 carbons),
135.3, 210.6; IR (neat) 520, 610, 660, 700, 730, 770, 850,
890, 910, 940, 970, 1050, 1060, 1120, 1160, 1220, 1230,
Compound 30b. Colorless viscous oil. [a]2D0 K64.7 (c 1.14,
CHCl3); 1H NMR (500 MHz, CDCl3) d 0.90 (3H, s, C-Me),
1.39 (3H, s, C-Me), 1.82 (1H, d, JZ11.4 Hz), 1.88 (1H, d,
JZ11.4 Hz), 2.15 (1H, dd, JZ1.8, 5.1 Hz), 2.46 (1H, d, JZ
5.0 Hz), 2.50 (1H, s), 2.94 (1H, t, JZ2.4 Hz), 4.55 (1H, t,
JZ2.5 Hz), 4.58 (1H, t, JZ2.3 Hz), 4.90 (1H, d, JZ
2.5 Hz), 6.55 (1H, s), 6.98–7.03 (2H, m, Ph), 7.22–7.27 (1H,
m, Ph), 7.32–7.46 (5H, m, Ph), 7.49–7.55 (2H, m, Ph); 13C
NMR (125 MHz, CDCl3) d 22.2, 26.5, 28.7, 30.3, 33.5,
33.6, 41.3, 45.2, 77.2, 79.1, 83.1, 83.9, 85.8, 110.5, 121.9 (2
carbons), 126.6, 128.1 (2 carbons), 128.9, 129.3 (2 carbons),
129.5 (2 carbons), 134.2, 153.4, 192.9, 202.7; IR (neat) 690,
750, 880, 1020, 1070, 1200, 1270, 1380, 1460, 1490, 1590,
1700, 2940, 2990 cmK1; HREIMS (m/z) calcd for
C28H26O6S (MC): 490.1450, found 490.1476.
1260, 1380, 1450, 1490, 1710, 2890, 2930, 2990 cmK1
;
EIMS (m/z) 466 (MC), 451 [(MKMe)C], 408 [(MK
Me2CO)C], 375 [(MKPhCH2)C]; HREIMS (m/z) calcd for
C21H23IO4 (MC): 466.0641, found 466.0636.
4.1.17.
(1R,2S,4S,5S,6R,7R,8R,9S,10S)-4-Benzyl-
6, 9-epoxy-4, 5-(O-isopropylidenedioxy)tetracy-
clo[6.2.1.02,7.02,10]undecan-3-one (31). Tri-n-butyltin
hydride (0.35 ml, 1.3 mmol) and azobisisobutyronitrile
(AIBN) (21 mg, 0.13 mmol) were added to a solution of
30 (6:1 epimeric mixture) (213 mg, 0.43 mmol) in dry
toluene (7.5 ml). For the deaeration of the reaction mixture,
it was frozen using liquid nitrogen, and the reaction vessel
was evacuated in vacuo for 30 min and then filled with dry
4.1.19. (1R,4S,4aR,5R,6S,7S,8aS)-7-Benzyl-5-hydroxy-
6,7-O-isopropylidenedioxy-1,4,4a,5,6,7,8,8a-octahydro-
endo-1,4-methanonaphthalen-8-one (33). Zinc powder
(272 mg, 4.2 mmol) and acetic acid (0.24 ml, 4.2 mmol)
were successively added to a stirred solution of 32 (130 mg,
0.28 mmol) in methanol (5 ml) at room temperature.

1602
T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
The mixture was gradually warmed to 60 8C and stirred for
1 h at the same temperature. After cooling, the mixture was
diluted with ether (80 ml) and filtrated. The filtrate was
washed with saturated aqueous sodium hydrogen carbonate
(2!30 ml), and brine (2!30 ml), then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 4:1) to give 33 (86 mg, 91%) as a white solid.
Recrystallization from hexane/dichloromethane (10:1)
afforded colorless prisms, mp 169–170 8C; [a]2D0 C161.0
(c 0.99, CHCl3); 1H NMR (500 MHz, CDCl3) d 0.79 (3H, s,
C-Me), 1.41 (1H, d, JZ8.4 Hz, C9–H), 1.47 (3H, s, C-Me),
1.54 (1H, d, JZ8.4 Hz, C9–H), 1.58 (1H, d, JZ3.2 Hz,
OH), 2.73 (1H, d, JZ14.4 Hz, CHaHbPh), 2.99 (1H, s,
C1–H), 3.21 (2H, m, C4–H, C8a–H), 3.41 (1H, d, JZ
14.4 Hz, CHaHbPh), 3.46 (1H, dd, JZ3.7, 11.6 Hz, C4a–H),
4.40 (1H, d, JZ4.6 Hz, C6–H), 4.45 (1H, q, JZ3.9 Hz,
C5–H), 6.20 (1H, dd, JZ2.9, 5.4 Hz, C2–H), 6.48 (1H, dd,
JZ3.1, 5.4 Hz, C3–H), 7.20 (1H, m, Ph), 7.28–7.26 (4H, m,
Ph); 13C NMR (125 MHz, CDCl3) d 26.5, 27.5, 38.8, 43.3,
43.5, 45.3, 47.2, 51.0, 68.1, 80.1, 83.2, 111.4, 126.3, 127.7
(2 carbons), 132.0 (2 carbons), 133.0, 136.6, 139.1, 207.6;
IR (KBr) 540, 620, 660, 700, 730, 750, 820, 850, 910, 980,
1060, 1080, 1150, 1170, 1220, 1240, 1260, 1340, 1380,
1450, 1500, 1710, 2940, 2990, 3520 cmK1; EIMS (m/z) 340
(MC), 325 [(MKMe)C], 282 [(MKMe2CO)C], 249 [(MK
PhCH2)C]. Anal. Calcd for C21H24O4: C, 74.09, H, 7.11.
Found: C, 74.01, H, 7.17.
acid (2!30 ml), saturated aqueous sodium hydrogen
carbonate (2!30 ml), and brine (2!30 ml), then dried
over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 1:1) to give 4
(63 mg, 85%) as a colorless viscous oil. [a]2D0 K62.6 (c
1.19, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.08 (3H, s, C-
Me), 1.30 (3H, s, C-Me), 2.86 (1H, d, JZ14.5 Hz,
CHaHbPh), 3.10 (3H, s, Ms), 3.27 (1H, d, JZ14.5 Hz,
CHaHbPh), 4.14 (1H, t, JZ1.7 Hz, C5–H), 5.45 (1H, dd, JZ
1.8, 4.8 Hz, C4–H), 6.30 (1H, d, JZ10.1 Hz, C2–H), 6.85
(1H, ddd, JZ1.8, 4.8, 10.1 Hz, C3–H), 7.25–7.34 (5H, m,
Ph); 13C NMR (125 MHz, CDCl3) d 26.3, 27.4, 38.1, 38.8,
71.2, 76.3, 81.6, 109.7, 127.3, 128.1 (2 carbons), 130.8,
131.4 (2 carbons), 134.1, 138.9, 197.8; IR (KBr) 530, 620,
700, 760, 790, 850, 900, 950, 980, 1070, 1090, 1120, 1150,
1180, 1230, 1370, 1450, 1500, 1690, 1740, 2940, 2990,
3030 cmK1; EIMS (m/z) 352 (MC), 337 [(MKMe)C], 294
[(MKMe2CO)C]; HREIMS (m/z) calcd for C17H20O6S
(MC): 352.0981, found 352.0982.
4.1.22. (1R,5S,6S)-5-Benzyl-5,6-dihydroxy-4-oxo-2-
cyclohexenyl methanesulfonate (35). A solution of 4
(60 mg, 0.17 mmol) in trifluoroacetic acid/water (6:1)
(1 ml) was stirred at 0 8C for 30 min. The mixture was
concentrated in vacuo to afford a residue, which was
purified by column chromatography (hexane/ethyl acetate,
1:1) to give 35 (45 mg, 85%) as a colorless viscous oil. [a]D20
K49.8 (c 0.95, CHCl3); 1H NMR (500 MHz, CDCl3) d 2.99
(1H, d, JZ3.6 Hz, C3–OH), 3.16 (3H, s, Ms), 3.18 (2H, s,
CH2Ph), 3.35 (1H, s, C6–OH), 4.14 (1H, dt, JZ1.1, 3.7 Hz,
C5–H), 5.47 (1H, dt, JZ1.1, 3.9 Hz, C4–H), 6.24 (1H, dd,
JZ1.1, 10.2 Hz, C2–H), 6.85 (1H, ddd, JZ1.1, 3.7,
10.2 Hz, C3–H), 7.14–7.19 (2H, m, Ph), 7.22–7.31 (3H,
m, Ph); 13C NMR (125 MHz, CDCl3) d 38.6, 40.9, 73.3,
75.7, 78.1, 127.3, 128.4 (2 carbons), 129.0, 130.6 (2
carbons), 134.1, 141.7, 197.1; IR (neat) 530, 700, 730,
780, 850, 880, 940, 980, 1060, 1110, 1170, 1360, 1440,
1450, 1490, 1690, 2930, 3030, 3480 cmK1; EIMS (m/z) 312
(MC), 294 [(MKH2O)C]; HREIMS (m/z) calcd for
C14H16O6S (MC): 312.0668, found 312.0656.
4.1.20. (4R,5S,6S)-6-Benzyl-4-hydroxy-5,6-O-isopropy-
lidenedioxy-2-cyclohexen-1-one (34). A stirred solution
of 33 (60 mg, 0.18 mmol) in diphenyl ether (4 ml) was
heated at 230 8C for 4 h. After cooling, the mixture was
concentrated in vacuo to afford a residue, which was
purified by column chromatography (hexane/ethyl acetate,
1:0/2:1) to give 34 (39.5 mg, 81%) as a colorless viscous
oil. [a]2D0 K0.7 (c 0.97, CHCl3); 1H NMR (500 MHz,
CDCl3) d 1.08 (3H, s, C-Me), 1.29 (3H, s, C-Me), 1.70 (1H,
d, JZ6.2 Hz, OH), 3.04 (1H, d, JZ14.1 Hz, CHaHbPh),
3.17 (1H, d, JZ14.1 Hz, CHaHbPh), 4.13 (1H, t, JZ1.8 Hz,
C5–H), 4.61 (1H, m, C4–H), 6.16 (1H, d, JZ10.1 Hz,
C2–H), 6.81 (1H, ddd, JZ2.0, 4.9, 10.1 Hz, C3–H), 7.25–
7.34 (5H, m, Ph); 13C NMR (125 MHz, CDCl3) d 26.1, 27.4,
38.9, 64.6, 78.5, 81.8, 108.6, 127.1, 127.8 (2 carbons),
128.3, 131.5 (2 carbons), 134.7, 144.4, 199.6; IR (neat) 530,
590, 620, 670, 700, 730, 760, 800, 830, 860, 900, 920, 970,
1030, 1060, 1080, 1110, 1140, 1170, 1230, 1240, 1380,
1440, 1450, 1500, 1680, 2930, 2990, 3030, 3060,
3450 cmK1; EIMS (m/z) 274 (MC), 259 [(MKMe)C];
HREIMS (m/z) calcd for C15H15O4 [(MKMe)C]: 259.0970,
found 259.0992.
4.1.23. (4S,5S,6S)-6-Benzyl-4,5-epoxy-6-hydroxy-2-
cyclohexen-1-one (2). 0.2 M Sodium hydroxide (0.7 ml,
0.14 mmol) was added dropwise to a stirred solution of 35
(30 mg, 96 mmol) in ether (8 ml) at 0 8C. After 10 min, the
mixture was extracted with ether (2!30 ml). The combined
extracts were washed with brine (3!20 ml) and dried over
Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography
(hexane/ethyl acetate, 2:1) to give 2 (19 mg, 90%) as a white
solid. Recrystallization from hexane/ether (5:1) afforded
colorless prisms, mp 96–97 8C; [a]2D0 C45.6 (c 0.80,
4.1.21. (1R,5S,6S)-5-Benzyl-5,6-O-isopropylidenedioxy-
4-oxo-2-cyclohexenyl methanesulfonate (4). Methanesul-
fonyl chloride (0.17 ml, 2.1 mmol) was added to a stirred
solution of 34 (58.8 mg, 0.21 mmol) in dichloromethane
(5 ml) containing triethylamine (0.42 ml, 3.0 mmol) and
4-dimethylaminopyridine (DMAP) (24 mg, 0.21 mmol) at
0 8C, and stirring was continued for 3 h at room
temperature. The reaction was quenched with saturated
aqueous sodium hydrogen carbonate (2 ml) at 0 8C, and the
mixture was diluted with ether (80 ml). The organic layer
was successively washed with 3% aqueous hydrochloric
1
CHCl3); H NMR (500 MHz, CDCl3) d 2.93 (1H, d, JZ
13.6 Hz, CHaHbPh), 3.01 (1H, d, JZ13.6 Hz, CHaHbPh),
3.60 (1H, dt, JZ1.6, 3.9 Hz, C4–H), 3.65 (1H, s, OH), 3.77
(1H, d, JZ3.9 Hz, C5–H), 6.16 (1H, dd, JZ1.5, 9.9 Hz,
C2–H), 7.09–7.15 (3H, m, Ph, C3–H), 7.22–7.32 (3H, m,
Ph); 13C NMR (125 MHz, CDCl3) d 44.4 (CH2Ph), 47.9 (C4
or C5), 56.0 (C4 or C5), 77.7 (C6), 127.3 (Ph or C3), 128.4
(2 carbons, Ph), 130.2 (Ph or C3), 130.3 (2 carbons, Ph),
133.6 (Ph), 145.1 (C2), 197.5 (C1); IR (KBr) 500, 540, 580,
630, 670, 700, 750, 790, 840, 860, 900, 960, 1030, 1090,

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1603
1130, 1150, 1200, 1240, 1250, 1300, 1380, 1450, 1490,
1600, 1690, 2850, 2920, 3030, 3060, 3480 cmK1; HREIMS
(m/z) calcd for C13H12O3 (MC): 216.0786, found 216.0806.
Anal. Calcd for C13H12O3: C, 72.21; H, 5.59. Found: C,
71.81; H, 5.58.
mixture was diluted with ether (200 ml). The organic layer
was washed successively with saturated aqueous sodium
thiosulfate (2!80 ml), saturated aqueous sodium hydrogen
carbonate (2!80 ml), and brine (2!80 ml), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography
(hexane/ethyl acetate, 2:1) to give 36 (389 mg, 88%) as a
white solid. Recrystallization from hexane/ether (5:1)
afforded colorless prisms, mp 252–253 8C; [a]2D0 K2.0 (c
1.12, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.19 (3H, s, C-
Me), 1.41 (3H, s, C-Me), 1.47 (3H, s, C-Me), 1.51 (3H, s, C-
Me), 1.79 (1H, d, JZ11.4 Hz, C11–H), 1.84 (1H, d, JZ
11.4 Hz, C11–H), 2.25 (1H, d, JZ5.2 Hz, C1–H), 2.42 (4H,
s, Me of Ts, C8–H), 2.65 (3H, s, S-Me), 2.72 (1H, dd, JZ
1.9, 5.2 Hz, C10–H), 2.88 (1H, t, JZ2.4 Hz, C7–H), 3.77
(1H, dd, JZ7.0, 9.5 Hz, C40–H), 4.46 (1H, dd, JZ1.4,
9.6 Hz, C50–H), 4.50 (1H, t, JZ2.7 Hz, C6–H), 4.52 (1H, t,
JZ2.2 Hz, C9–H), 4.57 (1H, d, JZ2.8 Hz, C5–H), 4.65
(1H, d, JZ5.9 Hz, C50–H), 6.88 (1H, s, CH–OCS2Me), 7.31
(2H, d, JZ8.2 Hz, Ar), 7.69 (2H, d, JZ8.3 Hz, Ar); 13C
NMR (125 MHz, CDCl3) d 19.3, 20.3, 21.5, 24.1, 25.8,
27.7, 28.7, 29.3, 30.5, 32.5, 41.4, 47.5, 58.6, 64.7, 75.6,
79.5, 80.9, 82.9, 87.4, 96.8, 109.4, 128.2 (2 carbons), 129.6
(2 carbons), 137.5, 143.4, 205.6, 214.0; IR (neat) 520, 550,
590, 650, 680, 730, 820, 880, 910, 940, 1060, 1100, 1150,
1180, 1210, 1250, 1350, 1370, 1460, 1710, 2880, 2940,
2990 cmK1; EIMS (m/z) 621 (MC), 606 [(MKMe)C].
Anal. Calcd for C29H35NO8S3: C, 56.02; H, 5.67; N, 2.25; S,
15.47. Found: C, 55.85; H, 5.69; N, 2.29; S, 15.31.
4.1.24. (1R,2S,4S,5S,6R,7R,8R,9S,10S)-6,9-Epoxy-4,5-
O-isopropylidenedioxy-4-[[(4R)-2,2-dimethyl-3-(p-
toluenesulfonyl)oxazolidin-4-yl]hydroxymethyl]te-
tracyclo[6.2.1.02,7.02,10]undecan-3-one (24). Lithium
bis(trimethylsilyl)amide in THF (1.0 M solution, 5.30 ml,
5.3 mmol) was added dropwise to a stirred solution of 25
(800 mg, 2.4 mmol) in dry THF (40 ml) at K78 8C under
argon. After 30 min, a solution of (R)-N-(p-toluenesulfo-
nyl)-N,O-isopropylidene serinal (9) (1.72 g, 6.0 mmol) in
dry THF (20 ml) was added slowly at K78 8C, and the
resulting mixture was further stirred for 1 h at the same
temperature. The reaction was quenched with saturated
aqueous ammonium chloride (3 ml) at K78 8C, and the
mixture was diluted with ether (300 ml). The organic layer
was washed successively with saturated aqueous
ammonium chloride (2!100 ml), saturated aqueous sodium
hydrogen carbonate (2!100 ml), and brine (2!100 ml),
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 2:1/1:1) to give 24
(1.27 g, 98%) (inseparable mixture, major/minorZ9:1) as a
1
colorless viscous oil. H NMR (500 MHz, CDCl3) d 1.38
(3H, s, C-Me), 1.39 (3H, s, C-Me), 1.44 (3H, s, C-Me), 1.68
(3H, s, C-Me), 1.79 (1H, d, JZ11.3 Hz, C11–H), 1.85 (1H,
d, JZ11.3 Hz, C11–H), 2.25 (1H, d, JZ5.2 Hz, C1–H),
2.35 (1H, dd, JZ1.8, 5.2 Hz, C2–H), 2.41 (3H, s, Me of Ts),
2.45 (1H, s, C8–H), 2.70 (1H, d, JZ6.8 Hz, OH), 2.900(1H,
t, JZ2.3 Hz, C7–H), 3.76 (1H, d, JZ6.4, 9.8 Hz, C4 –H),
4.20 (1H, d, JZ6.5 Hz, C50–H), 4.39 (1H, d, JZ7.0 Hz,
CH-OH), 4.51 (1H, dd, JZ1.3, 9.8 Hz, C50–H), 4.55 (1H, t,
JZ2.3 Hz, C9–H), 4.59 (1H, t, JZ2.8 Hz, C7–H), 5.05 (1H,
d, JZ3.1 Hz, C6–H), 7.30 (2H, d, JZ8.2 Hz, Ar), 7.68 (2H,
d, JZ8.2 Hz, Ar); 13C NMR (125 MHz, CDCl3) d 20.6,
21.5, 24.4, 26.1, 27.8, 28.8, 29.2, 30.5, 32.6, 41.2, 47.2,
59.6, 64.7, 73.0, 76.2, 78.9, 83.2, 88.1, 96.9, 109.6, 127.8 (2
carbons), 129.7 (2 carbons), 137.8, 143.5, 206.7; IR (neat)
550, 590, 680, 730, 820, 830, 880, 940, 1030, 1100, 1150,
1230, 1250, 1340, 1370, 1380, 1460, 1710, 2880, 2940,
2990, 3440 cmK1; HREIMS (m/z) calcd for C27H33NO8S
(MC): 531.1927, found 531.1903.
4.1.26. (1R,2S,4S,5S,6R,7R,8R,9S,10S)-6,9-Epoxy-4,5-O-
isopropylidenedioxy-4-[[(4R)-2,2-dimethyl-3-(p-toluene-
sulfonyl)oxazolidin-4-yl]methyl]tetracyclo[6.2.1.02,7.02,10]-
undecan-3-one (37). Tri-n-butyltin hydride (0.33 ml,
1.2 mmol) and triethylborane in hexane (1.0 M solution,
0.63 ml, 0.63 mmol) were added successively to a stirred
solution of 36 (384 mg, 0.62 mmol) in dry toluene (24 ml) at
room temperature. After 1 h, the mixture was concentrated
in vacuo to afford a residue, which was purified by column
chromatography (hexane/ethyl acetate, 1:0/2:1) to give
37 (303 mg, 95%) as a white solid. Recrystallization
from hexane/ether (5:1) afforded colorless prisms, mp
207–208 8C; [a]D20 C49.1 (c 1.04, CHCl3); 1H NMR
(500 MHz, CDCl3) d 1.34 (3H, s, C20-Me), 1.37 (3H, s,
C-Me), 1.40 (3H, s, C-Me), 1.67 (3H, s, C20-Me), 1.79 (1H,
d, JZ11.4 Hz, C11–H), 1.84 (1H, d, JZ11.4 Hz, C11–H),
2.20 (1H, dd, JZ10.9, 14.7 Hz, C4–CHaHb–C40), 2.29 (1H,
d, JZ5.3 Hz, C1–H), 2.41 (3H, s, Me of Ts), 2.46 (1H, s,
C8–H), 2.51 (1H, dd, JZ1.8,05.2 Hz, C10–H), 2.57 (1H, d,
JZ14.6 Hz, C4–CHaHb–C4 ), 2.89 (1H, t, JZ2.3 Hz,
C7–H), 3.67 (1H, m, C50–H), 4.12–4.18 (2H, m, C40–H,
C50–H), 4.34 (1H, d, JZ2.9 Hz, C5–H), 4.57 (2H, d, JZ
2.6 Hz, C6–H, C9–H), 7.28 (2H, d, JZ8.1 Hz, Ar), 7.65
(2H, d, JZ8.3 Hz, Ar); 13C NMR (125 MHz, CDCl3) d
20.0, 21.5, 24.0, 26.8, 27.8, 30.3, 30.5, 31.7, 41.4, 44.5,
47.0, 55.7, 69.2, 76.30, 77.2, 83.5, 84.9, 84.9, 96.6, 109.7,
127.5 (2 carbons), 129.6 (2 carbons), 138.0, 143.2, 207.2; IR
(neat) 520, 550, 600, 650, 680, 710, 840, 880, 920, 940,
1030, 1060, 1240, 1300, 1340, 1370, 1450, 1710,
2880, 2940, 2990 cmK1; EIMS (m/z) 500 [(MKMe)C];
CIMS (m/z) 516 [(MCH)C]. Anal. Calcd for C27H33NO7S:
C, 62.89; H, 6.45; N, 2.72; S, 6.22. Found: C, 62.59; H, 6.49;
N, 2.74; S, 6.25.
4.1.25. (1R,2S,4S,5S,6R,7R,8R,9S,10S)-6,9-Epoxy-4,5-O-
isopropylidenedioxy-4-[[(4R)-2,2-dimethyl-3-(p-toluene-
sulfonyl)oxazolidin-4-yl](methyldithiocarbonyloxy)-
methyl]tetracyclo[6.2.1.02,7.02,10]undecan-3-one (36).
Sodium bis(trimethylsilyl)amide in THF (1.0 M solution,
0.85 ml, 0.85 mmol) was added dropwise to a stirred
solution of 24 (378 mg, 0.71 mmol) in dry THF (20 ml) at
K78 8C under argon. After 30 min, carbon disulfide
(0.43 ml, 7.1 mmol) was added slowly to the mixture at
K78 8C, and stirring was continued for 1 h at the same
temperature. The resulting mixture was gradually warmed
to K50 8C over 1 h, and then iodomethane (0.54 ml,
7.1 mmol) was added slowly to the above mixture at
K78 8C. After 1 h, the mixture was gradually warmed to
K50 8C over 1 h. The reaction was quenched with saturated
aqueous ammonium chloride (3 ml) at 0 8C, and then the

1604
T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
4.1.27. (1S,2S,3S,4R,4aR,5R,6S,7S,8aR)-3,5-Epoxy-2-
iodo-6,7-O-isopropylidenedioxy-7-[(2S)-2-p-toluenesulf-
onylamino-3-hydroxypropyl]-1,2,3,4,4a,5,6,8a-octahy-
(125 MHz, CDCl3) d 21.5, 24.2, 27.3, 28.2, 30.5, 33.0,
36.8, 40.2, 41.0, 46.6, 47.7, 48.3, 55.6, 68.7, 75.9, 81.4,
81.9, 89.2, 96.9, 111.3, 127.8 (2 carbons), 129.5 (2 carbons),
138.0, 143.2, 209.9; IR (neat) 510, 550, 590, 650, 680, 710,
730, 820, 840, 920, 940, 1100, 1160, 1230, 1340, 1370,
1460, 1600, 1710, 1890, 2930, 2990 cmK1; HREIMS (m/z)
calcd for C26H31INO7S [(MKMe)C]: 628.0866, found
628.0853.
dro-endo-1,4-methanonaphthalen-8-one
(38).
Iodotrimethylsilane (82 ml, 0.46 mmol) was added dropwise
to a stirred solution of 37 (98 mg, 0.15 mmol) in carbon
tetrachloride (10 ml) at K20 8C under argon, and stirring
was continued at K10 8C for 3 h. The reaction mixture was
quenched with saturated aqueous sodium thiosulfate (2 ml)
at 0 8C, and then the mixture was diluted with chloroform
(80 ml). The organic layer was washed successively with
20% aqueous sodium thiosulfate (2!30 ml), saturated
aqueous sodium hydrogen carbonate (2!30 ml), and brine
(2!30 ml), then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/ethyl acetate, 1:1) to give
38 (104 mg, 91%) as a white amorphous solid. [a]2D0 C44.3
(c 1.09, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.31 (6H, s,
C-Me), 1.74 (1H,0d, JZ11.2 Hz, C9–H), 1.86 (1H, dd,0JZ
3.5, 15.5 Hz, C1 –H), 2.20–2.32 (3H, m, C9–H, C1 –H,
OH), 2.42 (3H, s, Me of Ts), 2.61 (1H, dd, JZ4.8, 10.5 Hz,
C8a–H), 2.75 (1H, br, C1–H), 2.87 (1H, br, C4–H),02.91
(1H, dt, JZ3.8, 10.5 Hz, C4a–H), 3.43 (1H, m, C2 –H),
3.67 (2H, t, JZ4.7 Hz, C30H2OH), 3.75 (1H, d, JZ1.9 Hz,
C2–H), 3.80 (1H, t, JZ2.6 Hz, C5–H), 4.17 (1H, d, JZ
2.4 Hz, C6–H), 4.60 (1H, d, JZ11.2 Hz, C3–H), 5.84 (1H,
d, JZ4.6 Hz, N–H), 7.27 (2H, d, JZ8.0 Hz, Ar), 7.70 (2H,
d, JZ8.2 Hz, Ar); 13C NMR (125 MHz, CDCl3) d 21.5,
28.2, 28.5, 32.4, 35.8, 36.5, 42.0, 44.3, 46.6, 48.1, 51.4,
66.3, 77.0, 82.8, 85.5, 88.2, 112.8, 127.6 (2 carbons), 129.3
(2 carbons), 137.42, 143.0, 210.6; IR (neat) 550, 670, 730,
810, 850, 920, 940, 1050, 1090, 1130, 1160, 1220, 1230,
1330, 1380, 1420, 1600, 1710, 2890, 2930, 2980, 3280,
3510 cmK1; HREIMS m/z for C23H27INO6S [(MK
CH2OH)C]: 572.0604, found 572.0604.
4.1.29. (1R,4S,4aR,5R,6S,7S,8aS)-5-Hydroxy-6,7-O-iso-
propylidenedioxy-7-[(4S)-2,2-dimethyl-3-(p-toluenesul-
fonyl)oxazolidin-4-yl]methyl-1,4,4a,5,6,7,8,8a-octa-
hydro-endo-1,4-methanonaphthalen-8-one (40). Zinc
powder (123 mg, 1.9 mmol) and acetic acid (0.11 ml,
1.9 mmol) were successively added to a stirred solution of
39 (81 mg, 0.13 mmol) in methanol (6 ml) at room
temperature. The mixture was gradually warmed to 60 8C
and stirred for 1 h at the same temperature. After cooling,
the mixture was diluted with ether (50 ml) and filtrated. The
filtrate was washed with saturated aqueous sodium
hydrogen carbonate (2!20 ml), and brine (2!20 ml),
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 2:1) to give 40
(64 mg, 98%) as a colorless viscous oil. [a]2D0 C127.1 (c
1
1.14, CHCl3); H NMR (500 MHz, CDCl3) d 1.39 (1H, m,
C9–H), 1.45 (3H, s, C-Me), 1.47 (3H, s, C-Me), 1.53 (4H, s,
C-Me, C9–H), 1.67 (3H, s, C-Me), 1.81 (1H, d, JZ2.3 Hz,
OH), 2.17 (1H, dd, JZ10.5, 14.0 Hz, C7–CHaHb–C40), 2.25
(1H, dd, JZ1.8, 14.4 Hz, C7–CHaHb–C40), 2.41 (3H, s, Me
of Ts), 2.98 (1H, s, C4–H), 3.13 (1H, s, C1–H), 3.21 (1H, dt,
JZ3.4, 11.7 Hz, C4a–H), 3.43 (1H, dd, JZ3.6, 11.7 Hz,
C8a–H), 3.60 (1H, dd, JZ5.5, 9.0 Hz, C50–H), 4.12 (1H, dd,
JZ1.8, 9.0 Hz, C50–H), 4.37 (1H, br, C5–H), 4.43 (1H, d,
JZ4.3 Hz, C6–H), 4.45 (1H, m, C40–H), 6.19 (1H, dd, JZ
3.0, 5.5 Hz, C3–H), 6.50 (1H, dd, JZ3.1, 5.6 Hz, C2–H),
7.27 (2H, d, JZ8.2 Hz, Ar), 7.85 (2H, d, JZ8.3 Hz, Ar);
13C NMR (125 MHz, CDCl3) d 21.5, 24.4, 26.5, 27.3, 30.1,
41.8, 43.1, 43.6, 45.5, 46.4, 51.2, 56.4, 68.1, 68.7, 83.0,
85.2, 96.9, 112.2, 127.7 (2 carbons), 129.4 (2 carbons),
132.7, 138.5, 140.0, 142.9, 207.6; IR (neat) 550, 600,
650, 680, 710, 730, 780, 830, 920, 1050, 1100, 1160,
1210, 1240, 1340, 1380, 1450, 1600, 1720, 1880, 2940,
2990, 3530 cmK1; HREIMS (m/z) calcd for C26H32NO7S
[(MKMe)C]: 502.1900, found 502.1869.
4.1.28. (1S,2S,3S,4R,4aR,5R,6S,7S,8aR)-3,5-Epoxy-2-iodo-
6,7-O-isopropylidenedioxy-7-[(4S)-2,2-dimethyl-3-(p-tolu-
enesulfonyl)oxazolidin-4-yl]methyl-1,2,3,4,4a,5,6,8a-octa-
hydro-endo-1,4-methanonaphthalen-8-one (39). p-
Toluenesulfonic acid (6 mg, 34 mmol) was added to a
stirred solution of 38 (100 mg, 0.17 mmol) in benzene
(6 ml) containing 2,2-dimethoxypropane (0.20 ml,
1.7 mmol) at room temperature. The mixture was gradually
warmed to 60 8C and stirred for 1 h at the same temperature.
After cooling, the mixture was diluted with ether (80 ml).
The organic layer was washed with saturated aqueous
sodium hydrogen carbonate (2!30 ml) and brine (2!
30 ml), then dried over Na2SO4. Concentration of the
solvent in vacuo gave a residue, which was purified by
column chromatography (hexane/ethyl acetate, 2:1) to give
39 (88 mg, 83%) as a colorless viscous oil. [a]2D0 C138.4 (c
0.97, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.37 (3H, s, C-
Me), 1.43 (3H, s, C-Me), 1.44 (3H, s, C-Me), 1.70 (3H, s, C-
Me), 1.83 (1H, d, JZ11.2 Hz, C9–H), 2.13 (1H, dd, JZ
10.7,14.8 Hz, C7–CH2–C40), 2.27 (1H, d, JZ11.2 Hz,
C9–H), 2.430 (3H, s, Me of Ts), 2.48 (1H, d, JZ4.6 Hz,
C7–CH2–C4 ), 2.89–2.98 (3H, m, C1–H, C4–H, C4a–H),
3.02 (1H, dd, J0Z4.9, 10.2 Hz, C8a–H), 3.67 (1H, dd, JZ
5.5, 8.1 Hz, C5 –H), 3.930 (1H, d, JZ2.1 Hz, C2–H), 4.16–
4.22 (2H, m, C5–H, C5 –H), 4.40–4.46 (2H, m, C40–H,
C6–H), 4.80 (1H, d, JZ5.1 Hz, C3–H), 7.32 (2H, d, JZ
8.0 Hz, Ar), 7.83 (2H, d, JZ8.3 Hz, Ar); 13C NMR
4.1.30. (4R,5S,6S)-4-Hydroxy-5,6-O-isopropylidene-
dioxy-7-[(4S)-2,2-dimethyl-3-(p-toluenesulfonyl)oxazoli-
din-4-yl]methyl-2-cyclohexen-1-one (41). A stirred
solution of 40 (23.0 mg, 44 mmol) in diphenyl ether (5 ml)
was heated at 230 8C for 2 h. After cooling, the mixture was
concentrated in vacuo to afford a residue, which was
purified by column chromatography (hexane/ethyl acetate,
1:0/1:1) to give 41 (5.0 mg, 25%) as a colorless viscous
oil. [a]2D0 C58.1 (c 0.46, CHCl3); 1H NMR (500 MHz,
CDCl3) d 1.27 (3H, s, C-Me), 1.39 (6H, s, C-Me, C-Me),
1.68 (3H, s, C-Me), 2.13 (1H, dd, JZ10.8, 14.5 Hz,
C6–CHaHb–C40), 2.42 (3H, s, Me of Ts), 2.43 (1H, d, JZ
14.5 Hz, C6–CHaHb–C40), 2.52 (1H, br, OH), 3.74 (1H,
ddd, JZ1.3, 5.4, 9.2 Hz, C50–H), 4.07 (1H, dd, JZ5.3,
10.7 Hz, C40–H), 4.09 (1H, d, JZ9.0 Hz, C50–H), 4.16 (1H,
t, JZ1.7 Hz, C5–H), 4.66 (1H, br, C4–H), 6.17 (1H, d, JZ
10.2 Hz, C2–H), 6.84 (1H, ddd, JZ2.0, 4.6, 10.1 Hz,

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1605
C3–H), 7.29 (2H, d, JZ8.0 Hz, Ar), 7.69 (2H, d, JZ8.3 Hz,
Ar); 13C NMR (125 MHz, CDCl3) d 21.5, 24.1, 26.7, 27.2,
30.3, 39.5, 55.3, 64.7, 69.2, 80.7, 83.8, 97.0, 109.5, 127.6 (2
carbons), 128.2, 129.6 (2 carbons), 137.7, 143.4, 143.6,
198.8; IR (neat) 550, 590, 650, 680, 710, 750, 830, 880, 910,
1040, 1100, 1160, 1230, 1340, 1370, 1460, 1490, 1600,
1680, 2880, 2940, 2990, 3470 cmK1; HREIMS (m/z) calcd
for C21H26NO7S [(MKMe)C]: 436.1430, found 436.1403.
4.1.32. (1S,2S,3S,4R,4aR,5R,6S,7S,8aR)-3,5-Epoxy-2-iodo-
6,7-O-isopropylidenedioxy-7-[(4S)-2-oxo-3-(p-toluenesulfo-
nyl)oxazolidin-4-yl]methyl-1,2,3,4,4a,5,6,8a-octahydro-
endo-1,4-methanonaphthalen-8-one (44). Iodotrimethylsi-
lane (68 ml, 0.48 mmol) was added dropwise to a stirred
solution of 43 (210 mg, 0.42 mmol) in carbon tetrachloride
(20 ml) at K20 8C under argon. After 1 h, the reaction was
quenched with saturated aqueous sodium thiosulfate (2 ml)
at K20 8C, and then the mixture was diluted with ether
(150 ml). The organic layer was washed successively with
20% aqueous sodium thiosulfate (2!80 ml), saturated
aqueous sodium hydrogen carbonate (2!80 ml), and brine
(2!80 ml), then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/ethyl acetate, 3:2) to give
44 (195 mg, 74%) as a white solid. Recrystallization from
hexane/ether (5:1) afforded colorless needles, mp 233–
234 8C; [a]2D0 C152.8 (c 1.04, CHCl3); 1H NMR (500 MHz,
CDCl3) d 1.35 (3H, s, C-Me), 1.41 (3H, s, C-Me), 1.85 (1H,
d, JZ11.3 Hz, C9–Ha), 2.05 (1H, dd, JZ10.7, 14.6 Hz,
C7–CHaHb–C40), 2.29 (1H, d, JZ11.1 Hz, C9–Hb), 2.45
(3H, s, Me of Ts), 2.89–2.95 (3H, m, C1–H, C4a-H,
C7–CHaHb–C40), 2.97–3.04 (2H, m, C4–H, C8a-H), 3.80
(1H, d, JZ2.4 Hz, C2–H), 4.29 (1H, t, JZ3.7 Hz, C5–H),
4.42 (1H, t, JZ9.0 Hz, C50–H), 4.45 (1H, d, JZ4.1 Hz,
C6–H), 4.56 (1H, dd, JZ4.4, 9.3 Hz, C50–H), 4.80 (1H, m,
C40–H), 4.85 (1H, d, JZ5.3 Hz, C3–H), 7.37 (2H, d, JZ
8.3 Hz, Ar), 7.96 (2H, d, JZ8.3 Hz, Ar); 13C NMR
(125 MHz, CDCl3) d 21.7, 27.1, 28.0, 32.2, 36.7, 39.9,
40.7, 46.9, 47.9, 48.3, 54.5, 68.8, 75.6, 80.8, 81.0, 89.3,
111.5, 128.5 (2 carbons), 129.8 (2 carbons), 134.8, 145.5,
152.5, 210.3; IR (KBr) 540, 570, 610, 670, 760, 820, 920,
1050, 1090, 1130, 1170, 1310, 1370, 1450, 1600, 1700,
1790, 2990 cmK1; EIMS (m/z) 629 (MC), 614 [(MK
Me)C]; HRCIMS (m/z) calcd for C25H29INO8S [(MCH)C]:
630.0659, found 630.0693. Anal. Calcd for C25H28INO8S:
C, 47.70; H, 4.48; N, 2.23; S, 5.09. Found: C, 47.78; H, 4.47;
N, 2.30; S, 4.82.
4.1.31. (1R,2S,4S,5S,6R,7R,8R,9S,10S)-6,9-Epoxy-4,5-O-
isopropylidenedioxy-4-[[(4S)-2-oxo-3-(p-toluenesulfon-
yl)oxazolidin-4-yl]methyl]tetracyclo[6.2.1.02,7.02,10]un-
decan-3-one (43). 1.0 M Hydrochloric acid (1.36 ml,
1.4 mmol) was added to a stirred solution of 37 (320 mg,
0.62 mmol) in THF (15 ml) at room temperature, and the
mixture was heated at 55 8C for 6 h. After cooling, the
mixture was neutralized with saturated aqueous sodium
hydrogen carbonate (ca. 20 ml), and the resulting mixture
was extracted with ether (3!50 ml). The combined extracts
were washed with brine (2!50 ml), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography
(hexane/ethyl acetate, 2:1) to give an equilibrium mixture
1
(290 mg) of 42a and 42b (1:1 by 500 MHz H NMR) as a
colorless viscous oil. This equilibrium mixture was directly
used for the following reaction without separation.
Trichloromethyl chloroformate (1.23 ml, 6.2 mmol) was
added dropwise to a stirred solution of the above
equilibrium mixture of 42a and 42b (290 mg, 0.61 mmol)
in dry THF (30 ml) containing pyridine (1.96 ml, 24 mmol)
at 0 8C, and the mixture was gradually warmed to room
temperature. After 2 h, the reaction was quenched with
saturated aqueous sodium hydrogen carbonate (5 ml) at
0 8C, and the mixture was diluted with ether (200 ml). The
organic layer was washed successively with 3% aqueous
hydrochloric acid (2!80 ml), saturated aqueous sodium
hydrogen carbonate (2!80 ml), and brine (2!80 ml), then
dried over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 3:2) to give 43
(209 mg, 67% in two steps) as a white solid. Recrystalliza-
tion from hexane/ether (5:1) afforded colorless needles, mp
174–175 8C; [a]D20 C27.5 (c 1.16, CHCl3); 1H NMR
(500 MHz, CDCl3) d 1.36 (3H, s, C-Me), 1.39 (3H, s, C-
Me), 1.82 (1H, d, JZ11.6 Hz, C11–H), 1.87 (1H, 0d, JZ
11.6 Hz, C11–H), 2.02–2.09 (1H, m, C4–CHaHb–C4 ), 2.25
(1H, dd, JZ1.8, 5.2 Hz, C10–H), 2.34 (1H, d, JZ5.1 Hz,
C1–H), 2.45 (3H, s, Me of Ts), 2.50 (1H, s, C8–H), 2.90
(1H, t, JZ2.2 Hz, C7–H), 2.92 (1H, d, JZ14.6 Hz,
C4–CHaHb–C40), 4.33 (1H, d, JZ3.0 Hz, C5–H), 4.37–
4.404 (2H, m, C40ZH, C50ZH), 4.57 (1H, d, JZ5.4 Hz,
C5 ZH), 4.60 (1H, t, JZ2.8 Hz, C6–H), 4.62 (1H, t, JZ
2.2 Hz, C9–H), 7.33 (2H, d, JZ8.4 Hz, Ar), 7.86 (2H, d, JZ
8.4 Hz, Ar); 13C NMR (125 MHz, CDCl3) d 20.6, 21.7,
26.8, 27.8, 30.3, 30.5, 32.1, 41.3, 43.3, 46.6, 54.6, 68.6,
76.2, 83.3, 83.9, 84.1, 110.3, 128.5 (2 carbons), 129.8 (2
carbons), 134.7, 145.7, 152.3, 205.8; IR (KBr) 540, 580,
620, 670, 750, 810, 840, 880, 920, 940, 990, 1030, 1070,
1090, 1140, 1170, 1220, 1250, 1300, 1370, 1600, 1710,
1790, 2880, 2940, 2990 cmK1; EIMS (m/z) 501 (MC), 486
[(MKMe)C]; HREIMS (m/z) calcd for C25H27NO8S (MC):
501.1457, found 501.1481.
4.1.33. (1R,4S,4aS,5R,6S,7S,8aS)-5-Hydroxy-6,7-O-iso-
propylidenedioxy-7-[(4S)-2-oxo-3-(p-toluenesulfonyl)ox-
azolidin-4-yl]methyl-1,4,4a,5,6,7,8,8a-octahydro-endo-
1,4-methanonaphthalen-8-one (45). Zinc powder
(300 mg, 4.6 mmol) and acetic acid (0.26 ml, 4.6 mmol)
were successively added to a stirred solution of 44 (194 mg,
0.31 mmol) in THF/methanol (1:1) (20 ml) at room
temperature. The mixture was gradually warmed to 60 8C
and stirred for 1 h at the same temperature. After cooling,
the mixture was diluted with ether (150 ml) and filtrated.
The filtrate was washed with saturated aqueous sodium
hydrogen carbonate (2!70 ml), and brine (2!70 ml), then
dried over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 3:2) to give 45
(148 mg, 95%) as a colorless viscous oil. [a]2D0 C155.9 (c
1
1.00, CHCl3); H NMR (500 MHz, CDCl3) d 1.41 (1H, d,
JZ8.4 Hz, C9–H), 1.50 (3H, s, C-Me), 1.53 (3H, s, C-Me),
1.56 (1H, d, JZ8.4 Hz, C9–H), 1.94 (10 H, s, OH), 2.30 (1H,
dd, JZ10.5, 14.2 Hz, C7–CHaHb–C4 ), 2.44 (3H, s, Me of
Ts), 2.72 (1H, dd, JZ2.1, 14.1 Hz, C7–CHaHb–C40), 3.01
(1H, s, C4–H), 3.14 (1H, s, C1–H), 3.25 (1H, dt, JZ3.2,
11.6 Hz, C4a–H), 3.44 (1H, dd, JZ3.6, 11.6 Hz, C8a–H),
4.17 (1H, t, JZ8.5 Hz, C50–H), 4.36 (1H, dd, JZ5.1,

1606
T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
9.3 Hz, C50–H), 4.44 (1H, s, C5–H), 4.59 (1H, d, JZ4.3 Hz,
C6–H), 4.92 (1H, m, C40–H), 6.20 (1H, dd, JZ3.0, 5.3 Hz,
C3–H), 6.49 (1H, dd, JZ3.1, 5.5 Hz, C2–H), 7.34 (2H, d,
JZ8.3 Hz, Ar), 7.95 (2H, d, JZ8.3 Hz, Ar); 13C NMR
(125 MHz, CDCl3) d 21.7, 26.3, 27.2, 41.1, 43.1, 43.7, 45.5,
46.1, 51.2, 54.8, 67.9, 69.2, 82.9, 84.0, 112.5, 128.5 (2
carbons), 129.8 (2 carbons), 132.9, 134.9, 139.6, 145.5,
152.8, 207.7; IR (neat) 540, 580, 610, 670, 700, 760, 820,
850, 920, 1050, 1090, 1120, 1170, 1210, 1250, 1310, 1380,
1450, 1600, 1720, 1780, 2940, 2990, 3540 cmK1; HREIMS
(m/z) calcd for C25H29NO8S (MC): 503.1614, found
503.1595.
6.89 (1H, ddd, JZ1.9, 5.0, 10.2 Hz, C3–H), 7.36 (2H, d, JZ
8.2 Hz, Ar), 7.88 (2H, d, JZ8.3 Hz, Ar); 13C NMR
(125 MHz, CDCl3) d 21.7, 26.8, 27.1, 38.5, 39.1, 54.0,
69.0, 69.7, 79.8, 80.9, 111.0, 128.4 (2 carbons), 129.9 (2
carbons), 130.9, 134.4, 138.9, 145.8, 152.2, 196.5; IR (neat)
540, 570, 600, 620, 670, 730, 760, 820, 860, 950, 990, 1060,
1090, 1130, 1170, 1230, 1370, 1600, 1690, 1790, 2930,
2990 cmK1; CIMS (m/z) 516 [(MCH)C]; HREIMS (m/z)
calcd for C20H22NO10S2 [(MKMe)C]: 500.0685, found
500.0696.
4.1.36. (1R,5S,6S)-5,6-Dihydroxy-4-oxo-5-[(4S)-2-oxo-3-
(p-toluenesulfonyl)oxazolidin-4-yl]methyl-2-cyclohexe-
nyl methanesulfonate (47). A solution of 5 (59.2 mg,
0.11 mmol) in trifluoroacetic acid/water (6:1) (3 ml) was
stirred at 0 8C for 30 min. The mixture was concentrated in
vacuo to give 47 (54.6 mg, quant.) as a colorless viscous oil.
[a]2D0 C25.9 (c 1.22, CHCl3); 1H NMR (500 MHz, CDCl3) d
2.25 (1H, dd, JZ10.0, 14.7 Hz, C6–CHaHb–C40), 2.30–2.40
(1H, br, OH), 2.45 (3H, s, Me of Ts), 2.50–2.90 (1H, br,
OH), 2.98 (1H, d, JZ14.6 Hz, C6–CHaHb–C40), 3.18 (3H,
s, Me of Ms), 4.20–4.27 (2H, m, C5–H, C40–H), 4.30 (1H,
dd, JZ4.4, 9.3 Hz, C50–H), 4.45 (1H, t, JZ8.8 Hz, C50–H),
5.47 (1H, t, JZ3.5 Hz, C4–H), 6.38 (1H, d, JZ10.2 Hz,
C2–H), 6.89 (1H, ddd, JZ1.3, 4.1, 10.2 Hz, C3–H), 7.37
(2H, d, JZ8.2 Hz, Ar), 7.87 (2H, d, JZ8.3 Hz, Ar); 13C
NMR (125 MHz, CDCl3) d 21.7, 38.8, 40.2, 53.6, 70.4,
74.8, 75.0, 77.0, 128.5 (2 carbons), 129.3, 130.0 (2 carbons),
134.2, 140.6, 146.1, 152.4, 198.0; IR (neat) 540, 570, 670,
730, 760, 820, 850, 940, 1090, 1170, 1360, 1600, 1700,
1780, 2360, 2930, 3480 cmK1; HRCIMS (m/z) calcd for
C18H22NO10S2 [(MCH)C]: 476.0685, found 476.0658.
4.1.34. (4R,5S,6S)-4-Hydroxy-5,6-O-isopropylidene-
dioxy-6-[(4S)-2-oxo-3-(p-toluenesulfonyl)oxazolidin-4-
yl]methyl-2-cyclohexen-1-one (46). A stirred solution of
45 (148 mg, 0.29 mmol) in diphenyl ether (15 ml) was
heated at 230 8C for 2 h. After cooling, the mixture
was concentrated in vacuo to afford a residue, which was
purified by column chromatography (hexane/ethyl acetate,
1:0/1:1) to give 46 (75.9 mg, 59%) as a colorless viscous
oil. [a]2D0 C80.9 (c 1.05, CHCl3); 1H NMR (500 MHz,
CDCl3) d 1.26 (3H, s, C-Me), 1.40 (3H, s, C-Me), 2.09 (1H,
dd, JZ11.0, 14.5 Hz, C6–CHaHb–C40), 2.20 (1H, d, JZ
5.3 Hz, OH), 2.44 (3H, s, Me of Ts), 2.92 (1H, dd, JZ2.2,
14.4 Hz, C6–CHaHb–C40), 4.19 (1H, t, JZ1.7 Hz, C5–H),
4.45 (2H, d, JZ6.2 Hz, C50–H2), 4.59 (1H, m, C40–H), 4.72
(1H, t, JZ4.7 Hz, C4–H), 6.19 (1H, d, JZ10.2 Hz, C2–H),
6.90 (1H, ddd, JZ1.9, 4.8, 10.1 Hz, C3–H), 7.34 (2H, d, JZ
8.2 Hz, Ar), 7.87 (2H, d, JZ8.2 Hz, Ar); 13C NMR
(125 MHz, CDCl3) d 21.7, 26.6, 27.2, 39.0, 54.3, 64.1,
69.2, 80.0, 83.2, 109.9, 128.0, 128.4 (2 carbons), 129.9 (2
carbons), 134.5, 144.7, 145.8, 152.5, 198.0; IR (neat) 540,
570, 600, 670, 760, 820, 910, 1040, 1090, 1130, 1170, 1230,
1380, 1490, 1600, 1680, 1790, 2930, 3480 cmK1; CIMS (m/
z) 438 [(MCH)C]; HREIMS (m/z) calcd for C19H20NO8S
[(MKMe)C]: 422.0910, found 422.0926.
4.1.37. (4S,5S,6S)-4,5-Epoxy-6-hydroxy-6-[(4S)-2-oxo-3-
(p-toluenesulfonyl)oxazolidin-4-yl]methy-2-cyclohexen-
1-one (3b). 0.2 M Sodium hydroxide (1.5 ml, 0.30 mmol)
was added dropwise to a stirred solution of 47 (54.5 mg,
0.11 mmol) in ether (5 ml) at 0 8C. After 20 min, the
mixture was extracted with ether (3!30 ml). The
combined extracts were washed with brine (3!30 ml)
and dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 1:1) to give 3b
(32.3 mg, 75%) as a white solid. Recrystallization from
hexane/dichloromethane (3:1) afforded colorless prisms,
4.1.35. (1R,5S,6S)-5,6-O-Isopropylidenedioxy-4-oxo-5-
[(4S)-2-oxo-3-(p-toluenesulfonyl)oxazolidin-4-yl]methyl-
2-cyclohexenyl methanesulfonate (5). Methanesulfonyl
chloride (73 ml, 0.93 mmol) was added to a stirred solution
of 46 (68.3 mg, 0.16 mmol) in dichloromethane (7 ml)
containing triethylamine (0.17 ml, 1.2 mmol) and
4-dimethylaminopyridine (38.0 mg, 0.31 mmol) at 0 8C,
and stirring was continued for 4 h at room temperature. The
reaction was quenched with saturated aqueous sodium
hydrogen carbonate (1 ml) at 0 8C, and the mixture was
diluted with ether (70 ml). The organic layer was
successively washed with 3% aqueous hydrochloric acid
(2!30 ml), saturated aqueous sodium hydrogen carbonate
(2!30 ml), and brine (2!30 ml), then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 1:1) to give 5 (66.8 mg, 83%) as a colorless
viscous oil. [a]D20 C47.3 (c 1.07, CHCl3); 1H NMR
(500 MHz, CDCl3) d 1.27 (3H, s, C-Me), 1.42 (3H, s, C-
Me), 2.10 (1H, dd, JZ10.8, 14.3 Hz, C6–CHaHb–C40), 2.45
(3H, s, Me of Ts), 2.91 (1H, dd, JZ2.2, 14.3 Hz,
C6–CHaHb–C40), 3.19 (3H, s, Me of Ms), 4.34 (1H, t, JZ
1.8 Hz, C5–H), 4.43 (1H, dd, JZ4.8, 9.4 Hz, C50–H), 4.46
(1H, t, JZ9.3 Hz, C50–H), 4.58 (1H, m, C40–H), 5.58 (1H,
dd, JZ1.7 Hz, C4–H), 6.34 (1H, d, JZ10.1 Hz, C2–H),
mp 224–225 8C; [a]D20 C153.3 (c 0.99, CHCl3); H NMR
1
(500 MHz, CD2Cl2) d 2.34 (1H, dd, JZ10.5, 14.2 Hz,
C6–CHaHb–C40), 2.45 (3H, s, Me of Ts), 2.51 (1H, dd,
JZ1.1, 14.2 Hz, C6–CHaHb–C40), 3.49 (1H, br, OH),
3.67 (2H, m, C4–H, C5–H), 4.16 (1H, m, C40–H), 4.34
(1H, dd, JZ4.6, 9.4 Hz, C50–H), 4.44 (1H, t, JZ9.1 Hz,
C50–H), 6.35 (1H, m, C2–H), 7.27 (1H, m, C3–H), 7.38
(2H, m, Ar), 7.80 (2H, m, Ar); 13C NMR (125 MHz,
CD2Cl2) d 21.9 (Me of Ts), 40.7 (C6–CH2–C40), 48.6
(C40), 53.7 (C4), 56.5 (C5), 70.5 (C50), 77.3 (C6), 128.7
(2 carbons, Ar), 130.3 (3 carbons, Ar, C2), 134.7 (C3),
145.9 (Ar), 146.6 (Ar), 152.4 (C20), 197.9 (C1); IR (KBr)
540, 570, 600, 670, 760, 840, 990, 1090, 1170, 1370,
1690, 1780, 2360, 2930, 3460 cmK1; HRCIMS (m/z)
calcd for C17H17NO7S [(MCH)C]: 380.0804, found
380.0786.

T. Katoh et al. / Tetrahedron 62 (2006) 1590–1608
1607
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Acknowledgements
We thank Dr. H. Kogen (Sankyo Co. Ltd) and Dr. T. Ogita
(Sankyo Co. Ltd) for many useful suggestions and
encouragement. We also thank Mr. Y. Ijuin (Sagami
Chemical Research Center) for the X-ray crystallographic
analysis of 3. This work was supported in part by Grants-in-
Aid for High Technology Research Program and Scientific
Research on Priority Areas 17035073 from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan.
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´ ´
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