Synthetic studies on kinamycin antibiotics: Elaboration of a highly oxygenated D ring

Article abstract of DOI:10.1016/S0040-4020(01)00145-4

The synthesis of the model compound of kinamycin antibiotics, which possesses correct relative configurations at C1-C4 on the D ring, is reported in detail. The key steps involved a Diels-Alder reaction of indenone (12) and a Danishefsky-type diene (13), and stereoselective construction of a tetraoxygenated D ring.

Full text of DOI:10.1016/S0040-4020(01)00145-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2717±2728
Synthetic studies on kinamycin antibiotics: elaboration of a highly
oxygenated D ring
Takuya Kumamoto,a Nobutaka Tabe,a Kentaro Yamaguchi,b Hiroshi Yagishita,a Hiromichi Iwasaa
and Tsutomu Ishikawaa,p
aFaculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
bChemical Analysis Center, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
Received 4 January 2001; accepted 31 January 2001
AbstractÐThe synthesis of the model compound of kinamycin antibiotics, which possesses correct relative con®gurations at C1±C4 on the
D ring, is reported in detail. The key steps involved a Diels±Alder reaction of indenone (12) and a Danishefsky-type diene (13), and
stereoselective construction of a tetraoxygenated D ring. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
for kinamycins, 4 for so-called prekinamycin) to diazonium
ones (2 for kinamycins, 8 for so-called prekinamycin) by the
re-examination of X-ray crystallographic analysis of (1)-a-
methylbutyrate of kinamycin D. At the same time,
Dmitrienko et al.13 independently reported the revision of
the structures of kinamycins and so-called prekinamycin
based on an alternative synthesis of a compound 5, and
®nally reached to the same conclusion that Gould et al.
proposed.
Kinamycins were isolated from the culture broth of
Streptomyces murayamaensis sp. nov. Hata et Ohtani by
Omura et al.1 in 1970.2 These antibiotics are strongly active
against gram-positive bacteria but less against gram-
negative ones. The structures had been characterized as
benzo[b]carbazoloquinone N-cyanamides (1) with a highly
oxygen-functionalized D ring by spectroscopic means,
chemical reactions3 and X-ray crystallographic analysis.4
On biosynthetic studies for kinamycins, Gould et al.5
reported the isolation of dehydrorabelomycin (3) and
prekinamycin (now called isoprekinamycin6) from S.
murayamaensis as minor metabolites, the former between
which was shown to be a precursor by the incorporation of
deuterated 3 into kinamycins. The latter metabolite was also
supposed to be a precursor, and the same benzo[b]carbazo-
loquinone skeleton as 1 was proposed for its structure such
as 4 by the resemblance of the spectral data to those of
kinamycins.7
However, in spite of the accepted structures 2 for kina-
mycins, Gould has doubted the diazonium structure 8 for
so-called prekinamycin due to some discrepancies between
a synthetic compound 8 and so-called prekinamycin.14 Quite
recently, Proteau, Gould and Dmitrienko et al.6 revised the
structure of so-called prekinamycin from benzo[b]¯uorene
skeleton 8 to benzo[a]¯uorene one 9 based on precise
examination of spectral data of a model compound with
the latter skeleton. Further, they proposed to name so-called
prekinamycin isolated by Gould et al. as isoprekinamycin
and a compound with the formula 8 as prekinamycin,
respectively.
Problems still remained for the determination of the sub-
stituent pattern at 11 position8 (atoms X and Y in 1). The
reported data of 13C NMR (dC 78.5 ppm)9 for N-cyanamide
structures of kinamycins poorly agreed with those of
N-cyanoindoloquinones (dC 104.7 ppm for 6, 103.6 ppm
for 7).10 Furthermore, the compound 4 was synthesized by
Echavarren et al.,11 however, it was not identical with
so-called prekinamycin isolated by Gould et al.5 Thus, in
1994, Gould et al.12 revised the N-cyanamide structures (1
Thus, there have been some confusion on structures of kina-
mycin derivatives. Therefore, it should be important to
determine the structure of kinamycins by the synthesis of
the compounds with the structure 2. We ®rst planned the
stereoselective synthesis of a model compound 10 as shown
in Scheme 1, in which Diels±Alder reaction between inde-
none 12 and Danishefsky diene 13 was involved as a key
step for the elaboration of a highly oxygenated cyclohexene
ring.15 In this paper, we in detail report the ®rst successful
construction of a 3,4,5,6-tetraoxygenated cyclohexene ring
with a correct relative con®guration (cis,trans,trans) in
kinamycin skeletons (Fig. 1).16
Keywords: kinamycins; antibiotics; Diels±Alder reaction; indenone; stereo-
selective dihydroxylation.
Corresponding author. Tel.: 181-43-290-2910; fax: 181-43-290-2910;
e-mail: benti@p.chiba-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00145-4

2718
T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
OR3
CH3
HO
O
R4O
4
3
O
CH3
Kinamycin R1 R2 R3 R4
6
5
OR2
D
7
8
2
A
B
C
D
H
H
Ac Ac Ac
Ac H
A
B
C
1
OR1
H
11X
9
10
Ac H Ac Ac
Ac H Ac H
OH
O
OH
Y
OH
O
N
3
1: X=N, Y=C
2: X=C-, Y=N+
O
HO
RO
O
HO
O
O
O
O
R
CH3
CH3
R
CH3
–
C
–
N
N
C
OH
N+
O
C
C
N+
OR'
O
OH
N
N
N
N
4: R = R' = H
5: R = Ac, R' = CH3
6: R = H
7: R = OAc
8
9
Figure 1. Proposed structures of kinamycins (1, 2) and related compounds (3±9).
OR3
CH3
OTMS
CH3
OCH3
R4O
4
BnO
BnO
BnO
3
H
5
OR2
OTMS
CH3
2
6
+
1
–
9C
OR1
7
H
8
N+
N
O
O
OCH3
10
11
12
13
(Bn = benzyl)
Scheme 1. Retrosynthesis of 10.
2. Results and discussion
O
Indenone 12 was prepared from indanone 1417 by dehydro-
silylation of the corresponding silyl enol ether 1518 in
palladium acetate [Pd(OAc)2]-p-benzoquinone system.19
Trials for the preparation of 12 with other procedures,
such as dehydrobromination of a-bromoketone and thermal
decompositions of a-sulfoxides, resulted in formation of
complex mixtures. Diels±Alder reaction of 12 and diene
1320 by re¯uxing in benzene proceeded smoothly to afford
endo adduct 11. The relative con®guration of 11 was
determined by NOE enhancements (Fig. 2). Trial for the
OTMS
H
CH3
H
OCH3
H
H
H
12.9%
15.4%
13.8%
12.2%
Figure 2. Selected NOE enhancements of 11.
BnO
BnO
BnO
a
b
(64%, 2 steps)
O
OTMS
O
14
15
12
OTMS
O
BnO
BnO
CH3
OH
H
H
CH3
c
d
(61%, 2 steps)
OCH3
OCH3
H
H
O
O
11
16
Scheme 2. Synthesis of a-hydroxyketone 16. (a) TMSCl, Et3N, DMF, 608C, 16 h; (b) Pd(OAc)2, p-benzoquinone, CH3CN, rt, 5 h; (c) 13, benzene, re¯ux, 2 h;
(d) m-CPBA, Na2HPO4, CH2Cl2, 08C, 3 h, and then rt, 5 h.

T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
2719
Figure 3. X-Ray crystallography of 16.
O
OTMS
CH3
OTMS
BnO
BnO
H
H
CH3
4a
9a
a
c
11
(87%)
R
O
O
19
17: R = H
b
(63% from 12)
18: R = OH
O
OH
O
HO
HO
H
O
BnO
BnO
BnO
H
H
4
CH3
CH3
CH3
d
e
f
(64%)
(72%)
(86%)
OH
O
20α: 4-α-OH
20β: 4-β-OH
OH
OH
21
O
O
22
Scheme 3. Synthesis of diketal 22. (a) CSA, CH2Cl2, 08C, 10 min; (b) O2 (1 atm), KF, DMSO, rt, 2 h; (c) TMSOTf, Et3N, CH2Cl2, 08C, 10 min; (d) (i) OsO4,
NMO, THF±H2O (20:1), 08C, 1 h, and then rt, 12 h; (ii) 10% HCl, CH3OH, rt, 2 min; (e) DIBAL±H, THF, 2788C, 1 h; (f) 2-methoxypropene, CSA, DMF, rt,
2 h.
diastereoselective epoxidation of 11 with m-chloro-
perbenzoic acid (m-CPBA) for introduction of an oxygen
function into the C2 position21 gave a-hydroxyketone 16.
However, X-ray crystallographic analysis22 showed that the
oxidation occurred at the convex face to produce an
undesired trans system between C1±C2 positions (Scheme
2, Fig. 3).
easily oxygenated by molecular oxygen (O2). Thus,
treatment of 17 in dimethylsulfoxide (DMSO) under O2
atmosphere in the presence of potassium ¯uoride (KF)23
afforded g-hydroxyenone 18 in 63% yield from 12. The
position of the hydroxy group introduced in 18 was deter-
mined by the observation of a cross peak between H-4a (dH
3.92 ppm) and C-9a (dC 78.5 ppm) in the HMBC experi-
ments. The enone 18 was converted to the corresponding
silyl dienol ether 19, which was hydroxylated by a catalytic
amount of osmium tetroxide (OsO4) in the presence of
Desilylation of 11 under an acidic condition gave enone 17.
A doubly activated position at C9a in 17 was found to be

2720
T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
N-methylmorpholine N-oxide (NMO) followed by acidic
work-up to afford a 5:1 mixture of 1,3-diols 20a and 20b.
The mixture was subjected to the reduction with diisobutyl-
aluminum hydride (DIBAL-H) in tetrahydrofuran (THF) at
2788C followed by recrystallization from ethanol to give
tetrol 21 derived from a major component. A desired stereo-
chemical relationship at C3 and C4 of 21 was con®rmed
by NOE experiments of the corresponding diketal 22
(Scheme 3, Fig. 4).
4.1%
5.3%
H
H
6.8%
7.2%
H
O
O
O
CH3
O
16.4%
11.6%
H
H
Kishi et al.24 have proposed that dihydroxylation in allyl
ether functions with OsO4 is generally controlled by con-
®guration at the allylic position. This could not be simply
Figure 4. Selected NOE enhancements of 22.
O
O
BnO
CH3
H
a
22
(98%)
OH
OH
O
O
23
21
b
O
O
O
O
(37%)
BnO
BnO
c
CH3
OH
H
H
CH3
(65%)
OH
OH
OH
OH
OH
24
25
Scheme 4. Synthesis of diol 23 and tetrol 25. (a) OsO4, NMO, THF±H2O (8:1), 08C, 1 h, and then rt, 24 h; (b) 2-methoxypropene, CSA, DMF, rt, 2 h; (c) OsO4,
NMO, THF±H2O (20:1), rt, 18 h.
Figure 5. X-Ray crystallography of 23.

T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
2721
applied to the diastereoselectivity in dihydroxylation of 22
with OsO4 because of the presence of two allylic alcohol
units (C3 and C9a) in 22, however, we expected the
dihydroxylation from the convex face, as in the case of
11, to produce a pentaoxygenated cyclohexane ring with
correct cis,trans,transcon®guration at C1 to C4. Treatment
of 22 with OsO4-NMO system gave diol 23, the undesired
stereochemistry of which was shown by X-ray crystal-
lography (Fig. 5). The same diastereoselectivity was also
observed even in the dihydroxylation of a less hindered
monoketal 24 (Scheme 4).25,26 These dihydroxylations
from concave sites may be caused by the signi®cant shield
of convex sites by a C9a±O bond in more planer conforma-
tion due to a ketal bridge between C3±C4 as shown in
Fig. 6a.
TBSO
BnO
OR
OTBS
CH3
OH
OH
RO
H
BnO
b
H
CH3
(91%)
OH
OR
OH
OTBS
27
21: R = H
26: R = TBS
a
(60%)
Scheme 5. Synthesis of triol 27. (a) TBSCl, imidazole, DMF, rt, 5 h, and
then 508C, 2.5 h; (b) OsO4, pyridine, 08C, 1 h, and then rt, 24 h.
OsO4
OsO4
OTBS
3
TBSO
Alternation of a protecting group from a cyclic functionality
to an acyclic and a bulky one, such as tert-butyldimethyl-
silyl (TBS) group, was expected to greatly change a
conformation. Protection of tetrol 21 with tert-butylchloro-
dimethylsilane (TBSCl) gave tri-TBS ether 26. Whereas
large coupling constants among H-3, H-4 and H-4a
(J3,4ˆ8.3 Hz, J4,4aˆ11.6 Hz) were observed in diketal 22,
in which oxygen functions at C3 and C4 should be ®xed
in diequatorial positions due to a ketal ring formation, a
small coupling constant (Jˆ3.7 Hz) between H-3 and H-4
and no coupling between H-4 and H-4a in 26 indicated
H
9
H
HO
O
H
O
OTBS
CH3
O
CH3
H
O
H
OsO4
Figure 6. Proposed mechanisms for dihydroxylation of 22 (a) and 26 (b).
OsO4
(a)
(b)
Figure 7. X-Ray crystallography of 27. Alkyl groups on TBS were omitted for clarity.

2722
T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
diaxial orientation of the OTBS groups at C3 and C4. In this
situation, the concave face of 26 would be severely shielded
by an axial C3-OTBS group and C9-H in the boat-like
conformation (Fig. 6b). Thus, treatment of tri-TBS ether 26
with stoichiometric amount27 of OsO4 in pyridine afforded
triol 27 with a desired relative con®guration,28 which was
con®rmed by the X-ray crystallography (Scheme 5, Fig. 7).
27 followed by partial desilylation with an equimolar
amount of tetrabutylammonium ¯uoride (TBAF) afforded
diol 29 as only one isomer. The structure of 29 was deter-
mined by the X-ray crystallography (Fig. 8). Oxidation of 29
with pyridinium dichromate (PDC) gave a-hydroxyketone
30, which was converted to the corresponding xanthate 31
by treatment with carbon disul®de (CS2) and iodomethane
(CH3I). Pyrolysis of 31 under vacuum smoothly proceeded
to yield a tetrahydro¯uorenone system 32. The enone 32
Selective ketal formation between C1± and C2±OH of triol
TBSO
BnO
TBSO
BnO
OTBS
CH3
OTBS
CH3
H
H
a
c
e
O
O
27
(78%)
(40%)
(98%)
O
O
OR
OH
OR
O
28: R = TBS
29: R = H
b
30: R = H
31: R = CS2CH3
d
(80%)
(54%)
TBSO
BnO
TBSO
BnO
TBSO
BnO
OTBS
OTBS
OTBS
CH3
CH3
CH3
f
g
O
O
O
(quant.)
(65%)
–
C
O
O
O
N+
O
N
H2N
N
32
33
34
Scheme 6. Synthesis of diazo compound 34. (a) 2,2-dimethoxypropane±acetone (5:1), p-TsOH´H2O, 608C, 19 h; (b) TBAF, THF, 08C, 15 min; (c) PDC,
CH2Cl2, rt, 24 h; (d) (i) NaH, THF, rt, 1 h, (ii) CS2, rt, 1 h, (iii) CH3I, rt, 1.5 h; (e) 3008C, 20 mmHg (Kugelrohr), 20 min; (f) NH2NH2´H2O, EtOH, re¯ux, 3 h;
(g) Ag2O, Et2O, then KOH in CH3OH, 08C, 1 h, and then rt, 2 h.
Figure 8. X-Ray crystallography of 29. Alkyl groups on TBS were omitted for clarity.

T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
2723
was treated with hydrazine hydrate in ethanol to afford
hydrazone 33 as (E)- and (Z)-isomers at a ratio of ca. 1:1,
which were easily isomerized each other to give ca. 1:1
mixtures. Conversion of a ca. 1:1 mixture of 33 to a diazo
system was successfully achieved with silver (I) oxide
(Ag2O) in the presence of potassium hydroxide (KOH)29
to give a desired 9-diazotetrahydro¯uorene 34 with correct
stereochemistries at C1±C4 (Scheme 6). The absorption at
2067 cm21 in the IR spectrum and the resonance at
66.1 ppm in the 13C NMR of 34 are in the range for those
of the typical diazo compounds.30
(9H, s, TMS), 3.28 (2H, d, Jˆ2.4 Hz, 1-H2), 5.16 (2H, s,
PhCH2O), 5.44 (1H, t, Jˆ2.4 Hz, 2-H), 6.81 (1H, d,
Jˆ8.1 Hz, 6-H), 7.03 (1H, d, Jˆ7.3 Hz, 4-H), 7.25 (1H,
dif. t, Jˆ7.5 Hz, 5-H), 7.32 (1H, d, Jˆ7.4 Hz, 40-H), 7.39
(2H, t, Jˆ7.4 Hz, 30-, 50-H), 7.45 (1H, d, Jˆ7.4 Hz, 20-,
60-H).
4.1.2. 4-Benzyloxy-1-indenone (12). A solution of 15
(5.41 g, 17.4 mmol) in CH3CN (20 mL) was added to a
solution of Pd(OAc)2 (1.88 g, 8.39 mmol) and p-benzo-
quinone (907 mg, 8.39 mmol) in CH3CN (60 mL) under
nitrogen (N2) and the mixture was stirred at room tempera-
ture (rt) for 2 h. After further addition of Pd(OAc)2 (950 mg,
4.23 mmol), the mixture was stirred at rt for 3 h. AcOEt
(80 mL) was added and precipitates were ®ltered off
through Celite pad. Evaporation of the AcOEt solution
followed by puri®cation by column chromatography (n-
hexane±AcOEtˆ30:1) gave 12 as an orange oil (2.54 g,
64% in 2 steps). IR n (CHCl3, cm21): 1700, 1615, 1600.
1H NMR (500 MHz) d: 5.14 (2H, s, PhCH2O), 5.78 (1H, d,
Jˆ5.8 Hz, 2-H), 6.99 (1H, d, Jˆ8.6 Hz, 5-H), 7.09 (1H, d,
Jˆ7.0 Hz, 7-H), 7.19 (1H, dd, Jˆ8.6, 7.0 Hz, 6-H), 7.30±
7.45 (5H, m, Ar±H), 7.80 (1H, d, Jˆ5.8 Hz, 3±H). EIMS
m/z: 236 (M1, 8.3%), 91 (100%).
3. Conclusions
In conclusion, we have succeeded in elaboration of highly
oxygenated D ring with correct stereochemistries for kina-
mycin skeletons. Currently our efforts continue to improve
ineffective steps and to complete the enantioselective total
synthesis of kinamycins.
4. Experimental
4.1. General
4.1.3. (^)-(1S,4aS,9aS)-5-Benzyloxy-1-methoxy-2-meth-
yl-1,4,4a,9a-tetrahydro-3-trimethylsilyloxy-9-¯uorenone
(11). A solution of 12 (2.12 g, 8.97 mmol) and 13 (4.01 g,
21.5 mmol) in dry benzene (20 mL) was re¯uxed for 2 h
under argon (Ar) and the solvent was evaporated. The
excess of 13 was distilled off under reduced pressure
(1108C, 20 mmHg) to give 11 (3.92 g) as an orange oil,
which was used to the next step without further puri®cation.
IR n (neat, cm21): 1717, 1676. 1H NMR (500 MHz) d: 0.14
(9H, s, TMS), 1.77 (3H, d, Jˆ2.5 Hz, 2-CH3), 2.55 (1H,
ddd, Jˆ14.9, 10.8, 2.5 Hz, 4-H), 2.85 (1H, dd, Jˆ14.9,
7.8 Hz, 4-H), 2.91 (1H, dd, Jˆ8.8, 4.6 Hz, 9a-H), 3.10
(3H, s, OCH3), 3.71 (1H, br ddd, Jˆ10.8, 8.8, 7.6 Hz, 4a-
H), 4.38 (1H, d, Jˆ4.6 Hz, 1-H), 5.10, 5.13 (each 1H, d,
Jˆ11.2 Hz, PhCH2O), 7.10 (1H, d, Jˆ7.8 Hz, 6-H), 7.31±
7.46 (7H, m, 7-, 8-, Ar±H).
All melting points were measured on a micro melting-point
hot stage (Yanagimoto) and uncorrected. IR spectra were
recorded on a JASCO FT/IR-300E spectrophotometer. H
1
NMR spectra were recorded in CDCl3 on JEOL JNM-
GSX400A (400 MHz), -GSX500A (500 MHz) or -ECP600
(600 MHz), using tetramethysilane (0.00 ppm) or residual
chloroform (CHCl3) (7.26 ppm) as an internal standard
unless stated otherwise. 13C NMR spectra were recorded
on JEOL JNM-GSX500A (125 MHz) or -ECP600
(150 MHz), using the middle resonance of CDCl3
(77.0 ppm) as an internal standard. EIMS were recorded
on a JEOL Automass with direct inlet or a Hewlett Packerd
5890 Series II Gas Chromatograph and 5971A Mass
Selective Detector with GC-MS. FABMS were recorded
on a JMS-HX110 with m-nitrobenzyl alcohol as a matrix.
Silica gel (Fuji Silysia FL100D) was used for column chro-
matography. Dichloromethane (CH2Cl2) was distilled from
phosphorus pentoxide (P2O5) before use. Chlorotrimethyl-
silane (TMSCl), N,N-dimethylformamide (DMF) and aceto-
nitrile (CH3CN) were distilled from calcium hydride
(CaH2). Pd(OAc)2 was puri®ed according to the reported
procedure.31 p-Benzoquinone was recrystallized from
benzene. Organic extract was dried over Na2SO4 before
evaporation.
4.1.4. (^)-(1S,2R,4aS,9aS)-5-Benzyloxy-1,2,3,4,4a,9a-hexa-
hydro-2-hydroxy-1-methoxy-2-methyl-3,9-¯uorenedione
(16). A solution of m-CPBA (80%, 78 mg, 0.36 mmol) in
CH2Cl2 (0.5 mL) was added to a suspension of 11 (153 mg,
0.36 mmol) and Na2HPO4 (81 mg, 0.57 mmol) in CH2Cl2
(1 mL) and the mixture was stirred at 08C for 3 h and then
at rt for 5 h. After addition of 10% Na2SO3 aq (5 mL), the
whole was extracted with AcOEt (3£10 mL). The combined
organic layer was washed with H2O (1£10 mL) and brine
(1£10 mL) and evaporated. Puri®cation of the residue by
column chromatography (n-hexane±AcOEtˆ1:1) gave 16
as colorless needles (78 mg, 61%, 2 steps from 12), mp
180±1838C, which were recrystallized from ethanol. IR n
4.1.1. 7-Benzyloxy-3-trimethylsilyloxyindene (15).
A
mixture of 4-benzyloxy-1-indanone (4.00 g, 16.8 mmol),
TMSCl (3.20 mL, 25.2 mmol) and triethylamine (5.36 mL,
38.4 mmol) in DMF (40 mL) was stirred at 608C for 16 h
under N2. After addition of saturated NaHCO3 aq (100 mL),
the whole was extracted with n-hexane (3£50 mL). The
combined organic layer was successively washed with
cold 5% HCl (1£30 mL), saturated NaHCO3 aq
(1£30 mL), H2O (1£30 mL) and brine (1£30 mL), and
evaporated to give 15 as an orange oil (5.41 g), which was
used to the next step without further puri®cation. IR n
1
(Nujol, cm21): 3377, 1721, 1687. H NMR (500 MHz) d:
1.42 (3H, s, CH3), 2.31 (1H, br s, OH), 2.77 (1H, dd,
Jˆ14.6, 12.6 Hz, 4-H), 3.30 (1H, dd, Jˆ14.6, 6.0 Hz,
4-H), 3.32 (1H, dd, Jˆ8.2, 4.4 Hz, 9a-H), 3.42 (3H, s,
OCH3), 3.88 (1H, ddd, Jˆ12.6, 8.2, 6.0 Hz, 4a-H), 4.14
(1H, d, Jˆ4.4 Hz, 1-H), 5.15, 5.18 (each 1H, d,
Jˆ12.2 Hz, PhCH2O), 7.11 (1H, dd, Jˆ8.0, 0.9 Hz, 6-H),
7.31±7.47 (7H, m, 7-, 8-, Ar±H). EIMS m/z: 366 (M1,
1
(CHCl3, cm21): 1610, 1580. H NMR (500 MHz) d: 0.30

2724
T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
3.6%), 91 (100%). Anal. Calcd for C22H22O5: C, 72.12; H,
6.05. Found: C,72.07; H, 6.17.
PhCH2O), 5.50 (1H, br s, 1-H), 5.67 (1H, d, Jˆ6.1 Hz,
4-H), 7.15 (1H, d, Jˆ8.0 Hz, 6-H), 7.26±7.48 (7H, m, 7-,
8-, Ar±H).
4.1.5. (^)-(4aS,9aS)-5-Benzyloxy-2-methyl-3,4,4a,9a-tetra-
hydro-3,9-¯uorenedione (17). Camphorsulfonic acid
(CSA) (431 mg, 1.85 mmol) was added to a solution of 11
(3.92 g, 9.28 mmol) in CH2Cl2 (40 mL) in one portion at
08C and the mixture was stirred at 08C for 10 min. After
addition of saturated NaHCO3 aq (20 mL), the aqueous
layer was separated and extracted with AcOEt (2£50 mL).
The combined organic layer was washed with H2O
(1£20 mL) and brine (1£20 mL) and evaporated to give
crude 17 as an orange oil (3.34 g), which was used to the
next step without further puri®cation. IR n (neat, cm21):
4.1.8. Dihydroxylation of the dienol 19 followed by
desilylation. OsO4 (17.8 mg, 7.0£1022 mmol) was added
to a suspension of 19 (671 mg, 1.40 mmol) and NMO
(97%, 237 mg, 1.96 mmol) in THF±H2O (20:1, 7 mL) at
08C. After stirring at 08C for 1 h and then at rt for 12 h,
the mixture was concentrated to ca. 1 mL and partitioned
with AcOEt (50 mL) and 10% Na2SO3 aq (50 mL). The
aqueous layer was extracted with AcOEt (2£50 mL). The
combined organic layer was washed with 10% Na2SO3 aq
(1£50 mL), H2O (1£50 mL) and brine (1£50 mL) and
evaporated. The residue was dissolved in methanol
(10 mL) and 10% HCl (0.5 mL) was added at rt. After
2 min, saturated NaHCO3 aq (50 mL) was added and the
whole was extracted with AcOEt (3£30 mL). The combined
organic layer was washed with H2O (1£30 mL) and brine
(1£30 mL) and evaporated. Puri®cation of the residue by
column chromatography (n-hexane±AcOEtˆ5:1±1:1) gave
a ca. 5:1 mixture of 20a and 20b as colorless prisms
(314 mg, 64%), which were used to the next step without
separation.
1
1710, 1680. H NMR (500 MHz) d: 1.83 (3H, s, 2-CH3),
2.61 (1H, dd, Jˆ16.2, 9.2 Hz, 4-H), 3.10 (1H, dd, Jˆ16.2,
7.3 Hz, 4-H), 3.56 (1H, m, 9a-H), 4.18 (1H, ddd, Jˆ9.2, 7.3,
7.3 Hz, 4a-H), 5.15, 5.20 (each 1H, d, Jˆ11.6 Hz,
PhCH2O), 6.85 (1H, dd, Jˆ4.6, 1.9 Hz, 1-H), 7.15 (1H, d,
Jˆ6.9, 2.0 Hz, 6-H), 7.30 (7H, m, 7-, 8-, Ar±H). 13C NMR
(125 MHz) d: 16.2 (CH3), 35.0 (C4a), 40.3 (C4), 49.5 (C9a),
70.3 (OCH2Ph), 116.4 (C6), 117.4 (C8), 127.4 (C20, C60),
128.3 (C40), 128.8 (C30, C50), 130.0 (C7), 136.0, 136.1,
136.4, 138.2 (C1), 144.5 (C2), 156.1 (C5), 198.0 (CˆO),
202.5 (CˆO). EIMS m/z: 318 (M1, 100%), 91 (94%).
4.1.9. (^)-(4S,4aS,9aS)-5-Benzyloxy-4,9a-dihydroxy-2-
methyl-3,4,4a,9a-tetrahydro-3,9-¯uorenedione (20a). A
part of the mixture was recrystallized from AcOEt to give
20a as colorless prisms, mp 140±1428C. IR n (Nujol,
4.1.6. (^)-(4aR,9aR)-6-Benzyloxy-9a-hydroxy-2-methyl-
3,4,4a,9a-tetrahydro-3,9-¯uorenedione (18). A solution of
crude 17 (3.04 g, 9.55 mmol) and KF (553 mg, 9.52 mmol)
in DMSO (30 mL) was stirred at rt for 2 h under O2. AcOEt
(300 mL) was added and the whole was washed by H2O
(100 mL). The aqueous layer was extracted with AcOEt
(2£100 mL). The combined organic layer was washed
with H2O (1£100 mL) and brine (1£100 mL) and evapo-
rated. Puri®cation of the residue by column chromatography
(n-hexane±AcOEtˆ10:1±3:1) gave 18 as colorless prisms
(1.72 g, 63%, 3 steps from 12), mp 128.5±129.58C, which
were recrystallized from ethanol. IR n (Nujol, cm21): 3464,
1726, 1657. 1H NMR (400 MHz) d: 1.76 (3H, d, Jˆ1.5 Hz,
2-CH3), 3.02 (1H, dd, Jˆ16.5, 7.3 Hz, 4-H), 3.15 (1H, br,
OH, exchangeable), 3.62 (1H, dd, Jˆ16.5, 3.0 Hz, 4-H),
3.92 (1H, ddd, Jˆ7.3, 3.0, 1.5 Hz, 4a-H), 5.14, 5.18
(each 1H, d, Jˆ11.5 Hz, PhCH2O), 6.28 (1H, dif. t,
Jˆ1.5 Hz, 1-H), 7.18 (1H, m, 6-H), 7.35±7.50 (7H, m, 7-,
8-, Ar±H). EIMS m/z: 334 (M1, 4.3%), 91 (100%). Anal.
Calcd for C21H18O4: C, 75.43; H, 5.43. Found: C, 75.39; H,
5.27.
1
cm21): 3376, 1702. H NMR (500 MHz) d: 1.91 (3H, d,
Jˆ1.2 Hz, 2-CH3), 2.91 (1H, br s, 9a-OH, exchangeable),
3.52 (1H, d, Jˆ3.7 Hz, 4-OH, exchangeable), 3.96 (1H, d,
Jˆ7.6 Hz, 4a-H), 4.50 (1H, dd, Jˆ7.6, 3.7 Hz, 4-H), 5.17,
5.23 (each 1H, d, Jˆ11.6 Hz, PhCH2O), 6.61 (1H, s, 1-H),
7.23±7.50 (8H, m, Ar±H). EIMS m/z: 350 (M1, 0.3%), 91
(100%). Anal. Calcd for C21H18O5: C, 71.99; H, 5.18.
Found: C, 72.05; H, 5.31.
4.1.10. (^)-(4R,4aS,9aS)-5-Benzyloxy-4,9a-dihydroxy-2-
methyl-3,4,4a,9a-tetrahydro-3,9-¯uorenedione (20b).
Recrystallization of the mother liquor from CH2Cl2 gave
20b as colorless prisms, mp 188±1918C. IR n (Nujol,
1
cm21): 3430, 3360, 1705, 1665. H NMR (400 MHz) d:
1.73 (3H, d, Jˆ1.5 Hz, 2-CH3), 3.22 (1H, br s, 9a-OH,
exchangeable), 4.00 (1H, dd, Jˆ5.1, 1.7 Hz, 4a-H), 4.61
(1H, d, Jˆ11.5 Hz, 4-OH, exchangeable), 5.06 (1H, dd,
Jˆ11.5, 5.1 Hz, 4-H), 5.18, 5.22 (each 1H, d, Jˆ11.0 Hz,
PhCH2O), 6.08 (1H, dq, Jˆ1.5, 1.5 Hz, 1-H), 7.23±7.50
(8H, m, Ar±H). EIMS m/z: 350 (M1, 1.3%), 332 (2.9%),
91 (100%). Anal. Calcd for C21H18O5: C, 71.99; H, 5.18.
Found: C, 71.79; H, 5.17.
4.1.7. (^)-(4aR,9aR)-5-Benzyloxy-4a,9a-dihydro-2-methyl-
3,9a-bis(trimethylsilyloxy)-9-¯uorenone (19). Trimethyl-
silyl tri¯uoromethanesulfonate (0.63 mL, 3.24 mmol) was
added to a solution of 18 (495 mg, 1.48 mmol) and triethyl-
amine (0.50 mL, 3.59 mmol) in CH2Cl2 (5 mL) at 08C. After
10 min, saturated NaHCO3 aq (10 mL) was added. The
aqueous layer was separated and extracted with AcOEt
(2£20 mL). The combined organic layer was washed with
H2O (1£10 mL) and brine (1£10 mL) and evaporated.
Puri®cation of the residue by column chromatography
(n-hexane±AcOEtˆ10:1) gave 19 as yellow prisms
(616 mg, 87%), mp 122±1248C. IR n (CHCl3, cm21):
1720. 1H NMR (400 MHz) d: 0.10, 0.15 (each 9H, s,
2£TMS), 1.74 (3H, d, Jˆ1.2 Hz, 2-CH3), 3.99 (1H, d,
Jˆ6.1 Hz, 4a-H), 5.14, 5.17 (each 1H, d, Jˆ12.2 Hz,
4.1.11. (^)-(3S,4S,4aS,9R,9aS)-5-Benzyloxy-2-methyl-3,
4,4a,9a-tetrahydro-3,4,9,9a-¯uorenetetrol (21). DIBAL-
H (1.0 M in hexane, 0.13 mL, 0.13 mmol) was added to a
solution of a ca. 5:1 mixture of 20a and 20b (22 mg,
6.3£1022 mmol) in THF (0.5 mL) at 2788C. After stirring
at 2788C for 1 h, 10% HCl (3 mL) was added and the whole
was extracted with AcOEt (3£5 mL). The combined organic
layer was washed with H2O (1£10 mL) and brine
(1£10 mL) and evaporated. Recrystallization of the residue
from ethanol gave 21 as colorless needles (16 mg, 72%), mp
1
208.5±210.58C. IR n (Nujol, cm21): 3430, 3371, 1592. H

T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
2725
NMR (500 MHz, CDCl3±CD3OD) d: 1.86 (3H, s, 2-CH3),
3.47 (1H, d, Jˆ11.3 Hz, 4a-H), 3.52 (1H, dd, Jˆ11.3,
7.3 Hz, 4-H), 4.26 (1H, d, Jˆ7.3 Hz, 3-H), 4.99 (1H, s, 9-
H), 5.10, 5.17 (each 1H, d, Jˆ11.3 Hz, PhCH2O), 5.62 (1H,
s, 1-H), 6.92 (1H, d, Jˆ8.2 Hz, 6-H), 7.07 (1H, d, Jˆ7.3 Hz,
8-H), 7.30 (1H, dif. t, Jˆ7.5 Hz, 7-H), 7.32±7.42 (5H, m,
Ar±H). FABMS m/z: 335 [(MH)1]. Anal. Calcd for
C21H22O5: C, 71.17; H, 6.26. Found: C, 70.99; H, 6.06.
0.10 mL, 0.99 mmol) in DMF (1 mL) was prepared. A part
of the solution (0.5 mL) was added to a solution of
21 (83 mg, 0.24 mmol) and CSA (2.6 mg, 1.1£1022
mmol) in DMF (3 mL) at rt. After stirring at rt for 2 h,
saturated NaHCO3 aq (10 mL) was added and the whole
was extracted with AcOEt (3£20 mL). The combined
organic layer was washed with H2O (1£10 mL) and brine
(1£10 mL) and evaporated. Puri®cation of the residue by
column chromatography (n-hexane±AcOEtˆ3:1±2:1) gave
crystalline product (65 mg),32 which was recrystallized from
AcOEt to give 24 (34 mg, 37%) as colorless needles, mp
191±1938C, in addition to diketal 22 (23 mg, 22%). IR n
4.1.12. (^)-(3S,4S,4aS,9R,9aS)-5-Benzyloxy-3,4;9,9a-bis-
(dimethylmethylenedioxy)-2-methyl-3,4,4a,9a-tetrahydro-
¯uorene (22). A solution of 2-methoxypropene (95%,
0.10 mL, 0.99 mmol) in DMF (0.60 mL) was prepared. 21
(22 mg, 5.9£1022 mmol) and CSA (2 mg, 8.6£1023 mmol)
were added to a part of the DMF solution (0.30 mL) and the
mixture was stirred at rt for 2 h. After addition of AcOEt
(20 mL), the whole was washed with saturated NaHCO3 aq
(1£15 mL). The aqueous layer was extracted with AcOEt
(2£10 mL). The combined organic layer was washed with
H2O (1£10 mL) and brine (1£10 mL) and evaporated.
Recrystallization of the residue from n-hexane gave 22 as
colorless needles (22 mg, 86%), mp 151±1558C. IR n
1
(Nujol, cm21): 3288, 1590. H NMR (500 MHz) d: 1.38,
1.54, 1.93 (each 3H, s, 3£CH3), 2.35 (1H, br s, 9a-OH,
exchangeable), 2.76 (1H, d, Jˆ9.8 Hz, 9-OH, exchange-
able), 3.45 (1H, dd, Jˆ11.9, 8.6 Hz, 4-H), 3.71 (1H, d,
Jˆ11.9 Hz, 4-H), 4.40 (1H, br d, Jˆ8.6 Hz, 3-H), 5.02
(1H, d, Jˆ9.2 Hz, 9-H), 5.06, 5.20 (each 1H, d,
Jˆ11.9 Hz, PhCH2O), 5.57 (1H, br s, 1-H), 6.88 (1H, d,
Jˆ8.2 Hz, 6-H), 7.04 (1H, d, Jˆ7.7 Hz, 8-H), 7.28 (2H,
m, 7-, 40-H), 7.36 (2H, d, Jˆ7.3, 7.3 Hz, 30-, 50-H), 7.60
(2H, dif. d, Jˆ7.3 Hz, 20-, 60-H). Anal. Calcd for C24H26O5:
C, 73.08; H, 6.64. Found: C, 72.74; H, 6.48.
1
(Nujol, cm21): 1592. H NMR (400 MHz) d: 0.84, 1.36,
1.48, 1.53 (each 3H, s, 4£CH3), 1.93 (3H, dd, Jˆ1.2,
1.2 Hz, 2-CH3), 3.27 (1H, dd, Jˆ11.6, 8.3 Hz, 4-H), 3.91
(1H, d, Jˆ11.6 Hz, 4a-H), 4.39 (1H, dq, Jˆ8.3, 1.2 Hz,
3-H), 5.09, 5.19 (each 1H, d, Jˆ11.9 Hz, PhCH2O), 5.40
(1H, s, 9-H), 5.49 (1H, dq, Jˆ1.2, 1.2 Hz, 1-H), 6.89 (1H,
d, Jˆ8.3 Hz, 6-H), 7.04 (1H, d, Jˆ7.3 Hz, 8-H), 7.27±7.47
(4H, m, 7-, 30-, 40-, 50-H), 7.62 (2H, d, Jˆ7.3 Hz, 20-, 60-H).
EIMS m/z: 435 [(M11)1, 0.2%], 434 (M1, 0.3%), 91
(100%). Anal. Calcd for C27H30O5: C, 74.63; H, 6.96.
Found: C, 74.84; H, 7.00.
4.1.15. (^)-(1S,2S,3S,4S,4aS,9S,9aS)-5-Benzyloxy-3,4-di-
methylmethylenedioxy-2-methyl-3,4,4a,9a-tetrahydro-
1,2,9,9a-¯uorenetetrol (25). OsO4 (1 mg, 3.9£1023 mmol)
was added to a mixture of 24 (11 mg, 2.8£1022 mmol) and
NMO (97%, 4.3 mg, 3.6£1022 mmol) in THF±H2O (20:1,
0.2 mL) at 08C. After stirring at rt for 6 h, NMO (97%,
4.3 mg, 3.6£1022 mmol) and OsO4 (1 mg, 3.9£1023
mmol) were added. After stirring at rt for 12 h, AcOEt
(10 mL) was added and the whole was washed with 10%
Na2SO3 aq (1£10 mL). The aqueous layer was extracted
with AcOEt (2£10 mL). The combined organic layer was
washed with 10% Na2SO3 aq (1£10 mL), H2O (1£20 mL)
and brine (1£20 mL) and evaporated. Recrystallization of
the residue from AcOEt±CH2Cl2 gave 25 as colorless
needles (8 mg, 65% as 1/2 hydrate), mp 191±1938C. IR n
4.1.13. (^)-(1R,2S,3R,4R,4aS,9R,9aR)-5-Benzyloxy-3,4;
9,9a-bis(dimethylmethylenedioxy)-2-methyl-1,2,3,4,4a,
9a-hexahydro-1,2-¯uorenediol (23). OsO4 (1.2 mg,
4.8£1023 mmol) was added to a mixture of 22 (16 mg,
3.7£1022 mmol) and NMO (97%, 6 mg, 5.0£1022 mmol)
in THF±H2O (8:1, 0.5 mL) at 08C. After stirring at 08C
for 1 h and then at rt for 24 h, AcOEt (10 mL) was added
and the whole was washed with 10% Na2SO3 aq (1£10 mL).
The aqueous layer was extracted with AcOEt (2£10 mL).
The combined organic layer was washed with H2O
(1£10 mL) and brine (1£10 mL) and evaporated. Recrystal-
lization of the residue from CH2Cl2±n-hexane gave 23 as
colorless prisms (17 mg, 98%), mp 178±1838C. IR n
1
(Nujol, cm21): 3411, 3298. H NMR (500 MHz) d: 1.37,
1.51, 1.52 (each 3H, s, 3£CH3), 2.10 (1H, br s, OH), 2.91
(1H, d, Jˆ6.8 Hz, 1-OH, exchangeable), 3.52 (1H, s, 9a-
OH, exchangeable), 3.53 (1H, d, Jˆ10.8 Hz, 3- or 4a-H),
3.56 (1H, d, Jˆ9.6 Hz, 3- or 4a-H), 3.76 (1H, dd, Jˆ10.8,
9.6 Hz, 4-H), 3.88 (1H, d, Jˆ6.8 Hz, 1-H), 5.07, 5.17 (each
1H, d, Jˆ12.4 Hz, PhCH2O), 5.69 (1H, d, Jˆ4.4 Hz, 9-H),
6.85 (1H, d, Jˆ8.4 Hz, 6-H), 7.03 (1H, d, Jˆ7.2 Hz, 8-H),
7.24±7.26 (4H, m, 7-, 30-, 40-, 50-H), 7.57 (2H, dif. d,
Jˆ7.2 Hz, 20-, 60-H). Anal. Calcd for C24H28O7´1/2 H2O:
C, 65.89; H, 6.68. Found: C, 66.07; H, 6.72.
1
(Nujol, cm21): 3530, 3412. H NMR (500 MHz) d: 0.92,
1.31 (each 3H, s, 2£CH3), 1.50 (9H, s, 3£CH3), 2.37 (1H, s,
2-OH, exchangeable), 2.87 (1H, d, Jˆ5.8 Hz, 1-OH,
exchangeable), 3.63 (1H, d, Jˆ9.8 Hz, 3- or 4a-H), 3.68
(1H, d, Jˆ10.4 Hz, 3- or 4a-H), 3.78 (1H, d, Jˆ5.8 Hz, 1-
H), 3.79 (1H, dd, Jˆ10.4, 9.8 Hz, 4-H), 5.10, 5.13 (each 1H,
d, Jˆ11.6 Hz, PhCH2O), 5.70 (1H, s, 9-H), 6.87 (1H, d,
Jˆ8.2 Hz, 6-H), 7.06 (1H, d, Jˆ7.3 Hz, 8-H), 7.23±7.30
(2H, m, 7-, 40-H), 7.34 (2H, dif. t, Jˆ7.7 Hz, 30-, 50-H),
7.57 (2H, dif. d, Jˆ7.0 Hz, 20-, 60-H). EIMS m/z: 469
[(M11)1, 0.1%], 468 (M1, 0.2%), 91 (100%). Anal. Calcd
for C27H32O7: C, 69.21; H, 6.88. Found: C, 68.81; H, 6.86.
4.1.16. (^)-(3R,4S,4aS,9R,9aS)-5-Benzyloxy-2-methyl-3,
4,4a,9a-tetrahydro-3,4,9-tris(tert-butyldimethylsilyloxy)-
9a-¯uorenol (26). A mixture of 21 (93.5 mg, 0.26 mmol),
TBSCl (199 mg, 1.32 mmol) and imidazole (126 mg,
1.85 mmol) in DMF (2 mL) was stirred at rt for 5 h and
then at 508C for 2.5 h under Ar. After addition of AcOEt
(30 mL), the whole was washed with cold 5% HCl
(2£10 mL), H2O (1£20 mL) and brine (1£20 mL), and
evaporated. Puri®cation of the residue by column chromato-
graphy (n-hexane±AcOEtˆ30:1±20:1) gave 26 as a color-
4.1.14. (^)-(3S,4S,4aS,9R,9aS)-5-Benzyloxy-3,4-dimethyl-
methylenedioxy-2-methyl-3,4,4a,9a-tetrahydro-9,9a-
¯uorenediol (24). A solution of 2-methoxypropene (95%,
1
less oil (109 mg, 60%), IR n (neat, cm21): 3511, 1595. H
NMR (500 MHz) d: 20.26 (3H, s, CH3), 20.05 (6H, s,

2726
T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
2£CH3), 20.04, 0.18, 0.21 (each 3H, s, 3£CH3), 0.53, 0.82,
dd, Jˆ8.3, 7.7 Hz, 7-H), 7.26±7.37 (5H, m, Ar±H). 13C
NMR (125 MHz) d: 25.1, 24.8, 24.4, 23.6, 23.4,
22.8, 17.8, 18.1, 18.5, 25.7, 25.8, 25.9, 26.5, 26.8, 28.4,
52.0, 69.8, 75.0, 76.0, 78.7, 78.8, 81.5, 81.9, 107.6, 111.8,
117.1, 126.7, 127.6, 128.4, 128.6, 131.3, 137.5, 143.1,
155.6. HRFABMS m/z: 793.4266 (Calcd for
C42H70O7Si3Na: 793.4327).
t
0.98 (each 9H, s, 3£ Bu), 1.83 (3H, d, Jˆ1.5 Hz, 2-CH3),
3.46 (1H, s, 4a-H), 3.81 (1H, d, Jˆ3.7 Hz, 3-H), 3.96 (1H,
br, 9a-OH), 4.40 (1H, d, Jˆ3.7 Hz, 4-H), 5.13 (1H, d,
Jˆ12.5 Hz, PhCH2O), 5.16 (1H, s, 9-H), 5.17 (1H, d,
Jˆ12.5 Hz, PhCH2O), 5.86 (1H, br s, 1-H), 6.67 (1H, d,
Jˆ8.2 Hz, 6-H), 6.73 (1H, d, Jˆ7.6 Hz, 8-H), 7.07 (1H,
dd, Jˆ8.2, 7.6 Hz, 7-H), 7.30 (1H, dif. t, Jˆ7.0 Hz, 40-H),
7.35 (2H, dif. t, Jˆ7.0 Hz, 30-, 50-H), 7.40 (2H, dif. d,
Jˆ7.4 Hz, 20-, 60-H). 13C NMR (125 MHz, CDCl3) d:
25.2, 25.12, 25.06, 24.7, 24.4, 24.2, 17.6, 17.8, 18.1,
22.5, 25.3, 25.7, 25.8, 56.8, 69.7, 71.5, 73.2, 76.3, 85.5,
111.0, 116.8, 127.4, 127.8, 128.3, 128.6, 130.1, 132.6,
134.8, 137.3, 143.8, 155.3. HRFABMS m/z: 735.3673
(Calcd for C39H64O5Si3K: 735.3699).
4.1.19. (^)-(1R,2R,3S,4S,4aS,9R,9aS)-5-Benzyloxy-3,4-
bis(tert-butyldimethylsilyloxy)-1,2-dimethylmethylene-
dioxy-1,2,3,4,4a,9a-hexahydro-2-methyl-9,9a-¯uorene-
diol (29). TBAF (1 M in THF, 0.11 mL, 0.11 mmol) was
added to a solution of 28 (28 mg, 3.6£1022 mmol) in THF
(0.5 mL) at 08C under Ar. After stirring at 08C for 15 min,
H2O (10 mL) and brine (5 mL) was added and the whole
was extracted with AcOEt (3£20 mL). The combined
organic layer was washed with H2O (1£10 mL) and brine
(1£10 mL) and evaporated. Puri®cation of the residue by
column chromatography (n-hexane±AcOEtˆ8:1) gave 29
as colorless needles (19 mg, 80%), mp 133±1348C, which
were recrystallized from n-hexane. IR n (CHCl3, cm21):
4.1.17. (^)-(1S,2S,3R,4S,4aR,9S,9aS)-5-Benzyloxy-1,2,3,
4,4a,9a-hexahydro-2-methyl-3,4,9-tris(tert-butyldimethyl-
silyloxy)-1,2,9a-¯uorenetriol
(27).
OsO4
(32 mg,
0.13 mmol) was added to a solution of 26 (80 mg,
0.11 mmol) in pyridine (1 mL) at 08C. After stirring at
08C for 1 h and then at rt for 24 h, NaHSO3 aq (119 mg,
1.14 mmol in 0.2 mL) was added and the whole was
extracted with AcOEt (3£15 mL). The combined organic
layer was washed with saturated NaHCO3 aq (1£10 mL),
H2O (1£10 mL) and brine (1£10 mL) and evaporated.
Puri®cation of the residue by column chromatography
(n-hexane±AcOEtˆ20:1) gave 27 (73 mg, 91%) as color-
less prisms, mp 132±133.58C, which were recrystallized
1
3568, 1593. H NMR (500 MHz) d: 20.31, 0.00 (each
t
3H, s, 2£CH3), 0.10 (6H, s, 2£CH3), 0.56 (9H, br s, Bu),
0.89 (9H, s, tBu), 1.46, 1.50, 1.56 (each 3H, s, 3£CH3), 3.01,
3.10 (each 1H, br, 2£OH, exchangeable), 3.56 (1H, s, 4a-H),
3.63 (1H, d, Jˆ2.8 Hz, 3-H), 4.26 (1H, br s, 4-H), 4.34 (1H,
s, 1-H), 5.08 (1H, br s, 9-H), 5.18, 5.21 (each 1H, d,
Jˆ15.2 Hz, PhCH2O), 6.64 (1H, d, Jˆ8.3 Hz, 6-H), 6.94
(1H, d, Jˆ7.7 Hz, 8-H), 7.06 (1H, dif. t, Jˆ8.0 Hz, 7-H),
7.26±7.47 (5H, m, Ar±H). FABMS m/z: 679 [(MNa)1], 657
[(MH)1]. Anal. Calcd for C36H56O7Si2: C, 65.81; H, 8.59.
Found: C, 65.57; H, 8.36.
from ethanol. IR n (Nujol, cm21): 3567, 3504. H NMR
1
(400 MHz) d: 20.13, 20.11 (each 3H, s, 2£CH3), 0.02
(9H, s, 3£CH3), 0.21 (3H, s, CH3), 0.50, 0.86, 0.88 (each
t
9H, s, 3£ Bu), 1.19 (3H, s, 2-CH3), 2.90 (1H, br, OH,
exchangeable), 3.25 (1H, s, OH, exchangeable), 3.33 (1H,
br s, 1-H), 3.65 (1H, br s, 4a-H), 3.68 (1H, d, Jˆ2.9 Hz,
3-H), 4.36 (1H, s, OH, exchangeable), 4.99 (1H, d,
Jˆ10.6 Hz, PhCH2O), 5.00 (1H, s, 9-H), 5.05 (1H, d,
Jˆ10.6 Hz, PhCH2O), 5.07 (1H, dd, Jˆ2.9 Hz, 1.2 Hz,
4-H), 6.79 (1H, d, Jˆ8.4 Hz, 6-H), 6.92 (1H, d, Jˆ7.5 Hz,
8-H), 7.11 (1H, dif. t, Jˆ7.9 Hz, 7-H), 7.34±7.36 (3H, m, 20-
, 40-, 60-H), 7.43±7.44 (2H, m, 30-, 50-H). FABMS m/z: 753
[(MNa)1]. Anal. Calcd for C39H66O7Si3: C, 64.06; H, 9.10.
Found: C, 64.17; H, 9.20.
4.1.20. (^)-(1R,2R,3S,4S,4aS,9aR)-5-Benzyloxy-1,2-di-
methylmethylenedioxy-1,2,3,4,4a,9a-hexahydro-9a-hy-
droxy-2-methyl-9-¯uorenone (30). PDC (98%, 335 mg,
0.87 mmol) was added to a solution of 29 (195 mg,
0.30 mmol) in CH2Cl2 (5 mL) at 08C. After stirring at rt
for 24 h, the mixture was diluted with diethyl ether (Et2O)
(20 mL). The precipitates were ®ltered off through Celite
pad and washed with Et2O. The ®ltrate and the washings
were combined and evaporated. Puri®cation of the residue
by column chromatography (n-hexane±AcOEtˆ20:1) gave
30 as colorless prisms (78 mg, 40%), mp 121.5±123.58C,
which were recrystallized from Et2O±n-hexane. IR n (KBr,
cm21): 3420, 1730. 1H NMR (500 MHz) d: 20.46, 20.06,
0.10, 0.12 (each 3H, s, 4£CH3), 0.53, 0.90 (each 9H, s,
4.1.18. (^)-(1R,2R,3R,4S,4aS,9R,9aR)-5-Benzyloxy-1,2-
dimethylethylenedioxy-1,2,3,4,4a,9a-hexahydro-2-methyl-
3,4,9-tris(tert-butyldimethylsilyloxy)-9a-¯uorenol (28). A
mixture of 27 (77 mg, 0.11 mmol), 2,2-dimethoxypropane
(0.8 mL, 6.5 mmol), acetone (0.2 mL, 2.72 mmol) and
p-toluenesulfonic acid hydrate (0.5 mg, 2.6£1023 mmol)
was stirred at 608C for 19 h. NaHCO3 powder (10 mg,
0.12 mmol) was added and the mixture was stirred at rt
for 30 min and evaporated. Puri®cation of the residue by
preparative TLC (n-hexane±AcOEtˆ10:1) gave 28 as a
t
2£ Bu), 1.37, 1.50, 1.57 (each 3H, s, 3£CH3), 3.06 (1H,
br, OH, exchangeable), 3.61 (1H, s, 3-H), 4.34 (1H, d,
Jˆ3.4 Hz, 4-H), 4.64 (1H, s, 1-H), 5.25, 5.28 (each 1H, d,
Jˆ14.1 Hz, PhCH2O), 6.99 (1H, d, Jˆ8.0 Hz, 6-H), 7.19
(1H, dd, Jˆ8.0 Hz, 7-H), 7.29±7.50 (6H, m, 8-, Ar±H).
FABMS m/z: 655 [(MH)1]. Anal. Calcd for C36H54O7Si2:
C, 66.02; H, 8.31. Found: C, 66.16; H, 8.34.
1
colorless oil (64 mg, 78%). IR n (CHCl3, cm21): 3493. H
NMR (500 MHz) d: 20.29, 0.00 (each 3H, s, CH3), 0.11
(6H, s, 2£CH3), 0.26, 0.28 (each 3H, s, 2£CH3), 0.67, 0.91,
4.1.21. (^)-(1S,2R,3R,4S,4aS,9aR)-O-[5-Benzyloxy-3,4-
bis(tert-butyldimethylsilyloxy)-1,2-dimethylmethylene-
dioxy-1,2,3,4,4a,9a-hexahydro-2-methyl-9-oxo-9a-¯uor-
enyl]-S-methyl dithiocarbonate (31). Solutions of CS2
(0.10 mL, 1.66 mmol) in THF (1 mL) and of CH3I
(0.10 mL, 1.61 mmol) in THF (1 mL) were prepared. A
solution of 30 (33 mg, 5.0£1022 mmol) in THF (1.5 mL)
was added to a suspension of NaH (60%, 10 mg,
t
0.97 (each 9H, s, 3£ Bu), 1.46 (3H, s, ketal CH3), 1.50 (3H,
s, 2-CH3), 1.60 (3H, s, ketal CH3), 3.63 (1H, d, Jˆ3.1 Hz,
3-H), 3.70 [2H (1H with D2O), br s, 4a-H, OH], 4.14 (1H, s,
1-H), 4.29 (1H, br d, Jˆ3.1 Hz, 4-H), 5.18, 5.21 (each 1H, d,
Jˆ14.6 Hz, PhCH2O), 5.24 (1H, s, 9-H), 6.61 (1H, d,
Jˆ8.3 Hz, 6-H), 6.75 (1H, d, Jˆ7.7 Hz, 8-H), 7.03 (1H,

T. Kumamoto et al. / Tetrahedron 57 (2001) 2717±2728
t
2727
0.25 mmol) in THF (0.5 mL) at 08C and the whole was
stirred at 08C for 1 h. A part of the CS2 solution (0.16 mL,
0.24 mmol) was added at 08C. After stirring at 08 C for 1 h, a
part of the CH3I solution (0.16 mL, 0.23 mmol) was added
at 08C. After stirring at 08C for 1.5 h, saturated NH4Cl aq
(10 mL) was added and the whole was extracted with
AcOEt (3£10 mL). The combined organic layer was
washed with H2O (1£10 mL) and brine (1£10 mL) and
evaporated. Puri®cation of the residue by preparative TLC
(n-hexane±AcOEtˆ20:1) gave 31 as a yellow oil (20 mg,
2£ Bu), 1.31, 1.42, 1.47 (each 3H, s, 3£CH3), 4.09 (1H, d,
Jˆ3.0 Hz, 3-H), 4.86 (1H, s, 1-H), 5.06 (1H, d, Jˆ3.0 Hz,
4-H), 5.22 (2H, s, PhCH2O), 6.61 (2H, br, NH2), 6.82 (1H, d,
Jˆ8.5 Hz, 6-H), 7.12 (1H, dif. t, Jˆ8.5 Hz, 7-H), 7.28±7.40
(6H, m, 8-, Ar±H).
4.1.24. (^)-(1R,2R,3R,4S)-5-Benzyloxy-3,4-bis(tert-butyl-
dimethylsilyloxy)-1,2-dimethylmethylenedioxy-9-diazo-2-
methyl-1,2,3,4-tetrahydro¯uorene (34). Ag2O (2.5 mg,
1.1£1022 mmol) was added to a suspension of 33 (2.5 mg,
3.8£1023 mmol) and Na2SO4 (10 mg) in dry Et2O (0.5 mL)
at 08C. After stirring at 08C for 30 min, 0.3% KOH in
CH3OH (0.2 mL) was added. After stirring at 08C for 1 h
and then at rt for 2 h, Et2O (2 mL) was added. The precipi-
tates were ®ltered off through Celite pad and washed with
Et2O. The ®ltrate and the washings were combined and
evaporated. Puri®cation of the residue by preparative TLC
(n-hexane±AcOEtˆ10:1) gave 34 as a colorless oil (1.6 mg,
1
54%). IR n (CHCl3, cm21): 1726. H NMR (500 MHz) d:
20.11, 20.07, 20.03, 0.03 (each 3H, s, 4£CH3), 0.71 (9H,
t
t
br s, Bu), 0.85 (9H, s, Bu), 1.39, 1.54, 1.56 (each 3H, s,
3£CH3), 2.50 (3H, s, SCH3), 3.86 (1H, d, Jˆ3.7 Hz, 3-H),
4.46 (1H, s, 4a-H), 4.56 (1H, s, 1-H), 4.80 (1H, dd,
Jˆ3.7 Hz, 1.8 Hz, 4-H), 5.14, 5.19 (each 1H, d,
Jˆ11.9 Hz, PhCH2O), 7.10 (1H, d, Jˆ8.0 Hz, 6-H), 7.19
(1H, dif. t, Jˆ8.0 Hz, 7-H), 7.34±7.39 (6H, m, 8-, Ar±H).
13C NMR (125 MHz) d: 24.8, 24.5, 24.34, 24.25, 18.1,
19.2, 23.8, 26.0, 26.1, 26.7, 27.4, 47.9, 70.6, 73.4, 79.5,
80.8, 82.1, 89.8, 109.2, 116.6, 118.1, 128.1, 128.5, 128.8,
129.5, 135.8, 136.9, 138.4, 155.8, 197.6, 211.2. HRFABMS
m/z: 745.3124 (Calcd for C38H57O7S2Si2: 745.3117).
1
65%). IR n (CHCl3, cm21): 2067. H NMR (600 MHz) d:
20.10, 0.01, 0.11, 0.12 (each 3H, s, 4£CH3), 0.79, 0.81
t
(each 9H, s, 2£ Bu), 1.14, 1.46, 1.48 (each 3H, s, 3£CH3),
4.08 (1H, d, Jˆ2.8 Hz, 3-H), 4.93 (1H, s, 1-H), 5.16 (1H, d,
Jˆ2.8 Hz, 4-H), 5.17, 5.25 (each 1H, d, Jˆ14.0 Hz,
PhCH2O), 6.63 (1H, dd, Jˆ6.6, 2.2 Hz, 8-H), 7.03±7.06
(2H, m, 6-, 7-H), 7.30 (1H, dif. t, Jˆ7.0 Hz, 40-H), 7.34
(2H, dif. t, Jˆ7.4 Hz, 30-, 50-H), 7.39 (2H, dif. d,
Jˆ6.9 Hz, 20-, 60-H). 13C NMR (150 MHz) d: 24.58,
24.57, 23.8, 23.6, 18.0, 18.3, 25.3, 25.9, 25.9, 28.7,
29.7, 30.0, 66.1, 69.0, 69.9, 76.2, 82.1, 106.8, 111.5,
111.7, 122.3, 124.0, 124.4, 127.8, 128.3, 128.6, 137.3,
154.5. HRFABMS m/z: 648.3395 (Calcd for
C36H52N2O5Si5: 648.3415).
4.1.22. (^)-(1R,2R,3R,4S)-5-Benzyloxy-3,4-bis(tert-butyl-
dimethylsilyloxy)-1,2-dimethylmethylenedioxy-2-methyl-
1,2,3,4-tetrahydro-9-¯uorenone (32). 31 (17 mg, 2.3£
1022 mmol) in Kugelrohr apparatus was heated at 3008C
for 20 min under vacuum (20 mmHg) to leave 32 as a
1
yellow oil (14 mg, 96%). IR n (CHCl3, cm21): 1708. H
NMR (500 MHz) d: 20.06, 0.06 (each 3H, s, 2£CH3),
t
0.12 (6H, s, 2£CH3), 0.71, 0.85 (each 9H, s, 2£ Bu), 1.32,
1.42, 1.45 (each 3H, s, 3£CH3), 4.03 (1H, d, Jˆ2.5 Hz,
3-H), 4.63 (1H, s, 1-H), 4.91 (1H, d, Jˆ2.5 Hz, 4-H),
5.16, 5.20 (each 1H, d, Jˆ12.8 Hz, PhCH2O), 6.92 (1H,
m, 6-H), 7.11±7.13 (2H, m, 7-, 8-H), 7.34±7.36 (5H, m,
Ar±H). 13C NMR (125 MHz) d: 24.7, 24.5, 23.9, 23.3,
17.9, 18.3, 25.0, 25.8, 25.9, 29.0, 29.9, 69.3, 70.9, 73.3,
75.5, 81.5, 111.3, 115.9, 119.5, 127.3, 128.2, 128.75,
128.80, 129.9, 130.7, 133.8, 136.3, 152.6, 155.9, 196.8.
HRFABMS m/z: 659.3198 (Calcd for C36H52O6Si2Na:
659.3200).
Acknowledgements
This research was partially supported by Scienti®c Research
Grants from the Ministry of Education, Science, Sports and
Culture of Japan.
References
4.1.23. (^)-(1R,2R,3R,4S)-5-Benzyloxy-3,4-bis(tert-butyl-
dimethylsilyloxy)-1,2-dimethylmethylenedioxy-2-methyl-
1,2,3,4-tetrahydro-9-¯uorenohydrazone (33). Hydrazine
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(6.8 mg, 1.1£1022 mmol) in ethanol (1 mL). After re¯uxing
for 3 h, the solvent was evaporated. Puri®cation of the resi-
due by preparative TLC (n-hexane±AcOEt ˆ 5:1) gave 3333
as geometrical isomers (less polar one: a yellow oil, 3.3 mg;
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1
cm21): 3440, 3300, 3210. H NMR (500 MHz) d: 20.07,
0.02, 0.11, 0.12 (each 3H, s, 4£CH3), 0.80, 0.81 (each 9H, s,
t
2£ Bu), 1.28, 1.46, 1.47 (each 3H, s, 3£CH3), 4.06 (1H, d,
Jˆ2.8 Hz, 3-H), 4.87 (1H, s, 1-H), 5.14 (1H, d, Jˆ2.8 Hz,
4-H), 5.16, 5.22 (each 1H, d, Jˆ13.1 Hz, PhCH2O), 6.72
(1H, d, Jˆ8.3 Hz, 6-H), 7.08 (1H, dif. t, Jˆ8.0 Hz, 7-H),
7.26±7.39 (6H, m, 8-, Ar±H). More polar isomer: Rf: 0.11
(n-hexane±AcOEtˆ5:1). IR n (neat, cm21): 3400, 3303,
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3230. H NMR (500 MHz) d: 20.02, 0.02 (each 3H, s,
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2£CH3), 0.12 (6H, s, 2£CH3), 0.815, 0.822 (each 9H, s,

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1
down®eld shift of 9-H compared to that of 24 in H NMR
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