Stereoselective approach to potential scaffold of A-nor B-aromatic OSW-1 analogues via [4+2] cycloaddition of o-quinodimethane

Article abstract of DOI:10.1016/j.tet.2014.04.079

A-nor B-aromatic steroidal skeleton was efficiently constructed by means of o-quinodimethane chemistry with exclusive stereoselectivity. The benzocyclobutene substrate for generation of the o-quinodimethane intermediate and subsequent [4+2] cycloaddition could be synthesized via (E)-selective Julia-Kocienski olefination and diastereoselective Grignard addition reactions. The synthesized tricyclic steroid-like compound with a trans-diol substructure would be utilized for divergent syntheses of potentially antitumor OSW-1 analogues with the truncated steroidal aglycone.

Full text of DOI:10.1016/j.tet.2014.04.079

Tetrahedron 70 (2014) 3981e3987
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective approach to potential scaffold of A-nor B-aromatic
OSW-1 analogues via [4þ2] cycloaddition of o-quinodimethane
Bozhi Li a, Seiji Masuda a, Daishiro Minato a, Dejun Zhou b, Kenji Sugimoto a,
,
Hideo Nemoto c, Yuji Matsuya a
*
a Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
b School of Physics and Chemistry, Henan Polytechnic University, Jiaozou 454000, China
c Lead Chemical Co. Ltd., 77-3 Himata, Toyama 930-0912, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2014
Received in revised form 25 April 2014
Accepted 26 April 2014
Available online 2 May 2014
A-nor B-aromatic steroidal skeleton was efficiently constructed by means of o-quinodimethane chem-
istry with exclusive stereoselectivity. The benzocyclobutene substrate for generation of the o-quinodi-
methane intermediate and subsequent [4þ2] cycloaddition could be synthesized via (E)-selective
JuliaeKocienski olefination and diastereoselective Grignard addition reactions. The synthesized tricyclic
steroid-like compound with a trans-diol substructure would be utilized for divergent syntheses of po-
tentially antitumor OSW-1 analogues with the truncated steroidal aglycone.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
o-Quinodimethane
JuliaeKocienski olefination
OSW-1
Steroidal skeleton
1. Introduction
o-Quinodimethanes, generated by thermolytic 4p-ring cleavage
of benzocyclobutene derivatives, have been extensively utilized in
an organic synthesis field as a highly useful and reactive in-
termediate.1 Complex organic molecules including fused polycyclic
system, such as a steroidal skeleton, have been assembled via an
intramolecular [4þ2] cycloaddition reaction of these intermediates
in a highly efficient manner. So-called ‘o-quinodimethane chemis-
try’ is undoubtedly one of the most important strategies for the
second-generation steroid syntheses.2 In our group, great efforts
have been devoted to this research field, and syntheses of tre-
mendous types of steroidal and steroid-like polycyclic compounds
have been accomplished and reported to date.3 Among them, we
have reported that trans-4,5-benzhydrindan-1-ones, such as 1
(Fig. 1) can be constructed by means of the o-quinodimethane
chemistry, in an efficient and stereoselective fashion, in which
trans-annulated CD ring and high enantio-purity are successfully
established.4 These compounds could be well adapted to convert-
ing into various A-nor steroidal bioactive compounds, including
aglycone of A-nor B-aromatic OSW-1 analogues 2.4,5
Fig. 1. Natural OSW-1 and its A-nor B-aromatic analogues.
OSW-1 (3) is known as an antitumor steroidal saponin, which
exhibits extremely potent cytotoxicity against wide range of ma-
lignant tumor cells, and expected to be a promising candidate of
novel anticancer drugs.6 In the course of our studies on SAR of
* Corresponding author. E-mail address: matsuya@pha.u-toyama.ac.jp (Y.
Matsuya).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.079

3982
B. Li et al. / Tetrahedron 70 (2014) 3981e3987
OSW-1, we have disclosed that simplification of the steroidal
skeleton of OSW-1 can be an effective approach for new antitumor
drug discovery, exemplified as A-aromatic (estrane) analogue7 and
des-AB-type analogue of OSW-1.8 In this context, A-nor B-aromatic
OSW-1 analogues 2 seem to be the next design of artificial com-
pounds having a truncated aglycone part, which is accessible
starting from trans-4,5-benzhydrindan-1-ones 1, synthesized by
the o-quinodimethane chemistry, as mentioned above.4 This
transformation, however, involves some embarrassing situations,
such as circuitous installation of the trans-diol unit via a multi-step
sequence.4a These drawbacks would be circumvented employing
more suitably functionalized benzocyclobutene substrate for the o-
quinodimethane chemistry, which will bring about straightforward
construction of the CD ring with the trans-diol unit. Thus, we set
compound 4 (Fig. 1) as a potential scaffold for various A-nor B-ar-
omatic OSW-1 analogues containing protected secondary alcohol
(on the C16 as steroidal numbering) and convertible primary al-
cohol (on the C22). The compound 4 should be a useful precursor of
a wide variety of OSW-1 analogues (2) possessing various oxidation
states at the C22 position, which would provide useful information
on SAR of the side-chain.9
Scheme 2. Preparation of the Julia substrates 7 and 8.
With the aldehyde 7 and the sulfones 8 in hand, we examined
modified Julia coupling of these compounds, and the results are
summarized in Table 1. In general, modified Julia olefination could
be expected to show (E)-selectivity11 desired in this synthesis. We
commenced the examination using BT sulfone 8a and NaHMDS as
a base in several solvents at ꢀ78 ꢁC (entries 1e3). Although the
reaction proceeded to give the coupling product 6, the yields were
moderate with low stereoselectivity. It has been reported that the
selectivity is significantly influenced by surroundings of the
Synthetic plan for the target compound 4 is presented in
Scheme 1. Tricyclic framework will be constructed at a time by
successive pericyclic reactions (4
p-ring cleavage and [4þ2] cyclo-
addition) via o-quinodimethane intermediate, generated from
highly oxygenated benzocyclobutene derivative 5. The transition
state of the [4þ2] cycloaddition will be dictated by the most relaxed
orientation of the substituents depicted in Scheme 1. The benzo-
cyclobutene 5 will be obtained by Sharpless asymmetric dihy-
droxylation (AD)10 followed by several transformations of alkene 6,
which will be synthesized by stereoselective modified Julia olefi-
nation reaction11 between aldehyde 7 and sulfone 8. In this paper,
we describe the stereoselective synthesis of 4, a core structure of A-
nor B-aromatic OSW-1, especially emphasizing good applicability
of the o-quinodimethane chemistry.
counter cation of the
a-sulfonyl carbanion (derived from the
base).15 Actually, these findings have been put to effective use for
enhancement of (E)-selectivity of modified Julia olefination by
adding several chelating agents.16 Thus, we tried addition of HMPA
or crown ether to improve the stereoselectivity (entries 4e6). Al-
though addition of HMPA brought no positive effects, it was found
that 18-crown-6 significantly improved (E)-selectivity of the re-
action.17 However, the chemical yields were still moderate and not
so satisfactory. Then, we examined JuliaeKocienski olefination us-
ing PT sulfone 8b, which was known to be easier to avoid self-
condensation under basic conditions (entries 7e9).16a Expectedly
the chemical yields were increased, and almost exclusive (E)-se-
lectivity was obtained when adding crown ether similar to the case
of 8a. Use of 1 equiv of 18-crown-6 gave rise to the best result (entry
8). Effects of crown ether for the enhancement of (E)-selectivity of
JuliaeKocienski olefination have been reasonably explained in the
past literature.16a The explanation is based on the prevention of
a closed transition state of the reaction between the sulfonyl
carbanion and the aldehyde, which includes a fixed chair-form
containing metal chelation leading to the (Z)-alkene product.
Table 1
Modified Julia olefination between aldehyde 7 and sulfone 8
Scheme 1. Synthetic plan for the target compound 4.
Entrya
Sulfone
Solvent
Additive (equiv)
Yield%b (E/Z)c
1
2
3
4
5
6
7
8
9
8a (BT)
8a (BT)
8a (BT)
8a (BT)
8a (BT)
8a (BT)
8b (PT)
8b (PT)
8b (PT)
THF
Et2O
d
37 (60:40)
55 (60:40)
62 (65:35)
61 (60:40)
46 (90:10)
56 (85:15)
82 (60:40)
83 (>95:5)
62 (>95:5)
2. Results and discussion
d
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
d
Already reported benzocyclobutenyl aldehyde 712 was pre-
pared as follows; readily available 1-cyano-4-methoxy
benzocyclobutene 913 was reduced by DIBAL, and the resulting
aldehyde was reacted with methoxymethylene phosphorane fol-
lowed by acid treatment to afford the homologated aldehyde 7 in
good yields. On the other hand, known optically pure alcohol 1014
was transformed into the two types of heteroarylsulfone 8a
(benzothiazolyl; BT) and 8b (phenyltetrazolyl; PT) through Mit-
sunobu reaction and subsequent oxidation of the hetero-
arylsulfides (Scheme 2).
HMPA (5)
18-crown-6 (1)
18-crown-6 (1)
d
18-crown-6 (1)
18-crown-6 (2)
a
All reactions were carried out using 1.2 equiv of aldehyde, 1 equiv of sulfone,
and 1.1 equiv of NaHMDS.
b
Isolated yields.
c
The ratio were estimated by 1H NMR spectra of a mixture of geometric isomers
(d
5.56, J¼15.0 Hz for E, and
d
5.24, J¼11.0 Hz for Z).

B. Li et al. / Tetrahedron 70 (2014) 3981e3987
3983
Under the influence of a high metal-abstracting character of the
crown ether, the reaction proceeds via an opened transition state
with the least steric repulsion between substituents on the sulfone
and the aldehyde, and then (E)-isomer is preferably produced.16a
Transformation of the compound 6 into the thermal reaction
substrate 5 is presented in Scheme 3.18 Stereoselective introduction
of two hydroxyl groups onto the alkene of 6 was achieved utilizing
Sharpless asymmetric dihydroxylation. Namely, the alkene 6 was
removed spontaneously by exposure to trifluoroborane and thio-
phenol to afford the triol 16 in a nearly quantitative yield. Because
the primary alcohol moiety was intended to further transform into
various side-chain in future, only the secondary hydroxyl group of
16 was protected as TBS ether through the two-step sequence, in-
stallation of the TBS group to both alcohol followed by removal of
one on the primary alcohol by mild treatment with AcOH. Thus,
highly efficient synthesis of the tricyclic system 4 containing five
stereogenic centers was accomplished in 11 steps from known
benzocyclobutenyl aldehyde 7 with 31.7% overall yield. This com-
pound would be a very important scaffold for a variety of OSW-1
analogues with A-nor B-aromatic steroidal aglycone.
reacted with AD-mix-a in the presence of methanesulfonamide to
give the diol 11 as a sole diastereomer in 82% yield.19 The next task
was selective protection of one hydroxyl group far from the methyl
group. After many complications, this was accomplished using
a sterically-demanding triisopropylsilyl (TIPS) group as a protecting
group. The other remaining hydroxyl group was then oxidized
upon treatment with TPAP to afford the ketone 12. Attempt to
convert 12 directly to 5 (P¼TIPS) via Grignard addition was un-
successful probably due to steric hindrance of the TIPS group.
Therefore, we had to change the bulky TIPS group to a less hindered
group, and we chose the methoxymethyl (MOM) group to this end
because of the assumption that a chelating ability of the MOM
group would work well for realizing the desired diaster-
eoselectivity of the subsequent Grignard addition reaction. Two
silyl groups (TBS and TIPS) were removed by exposure to TBAF, and
only the primary hydroxyl group was re-protected by the TBS group
under mild conditions to form the secondary alcohol 13, which was
then methoxymethylated to give the MOM ether 14. As expected,
the isopropenyl Grignard addition reaction of 14 proceeded at
ꢀ78 ꢁC in 91% yield with exclusive stereoselectivity to furnish re-
quired product 5. The stereochemical outcome could be reasoned
considering a simple chelation model.20
Scheme 4. Completion of synthesis of the target compound 4.
Fig. 2. Possible exo transition states for [4þ2] cycloaddition.
3. Conclusion
In summary, we have established an efficient synthetic approach
for the A-nor B-aromatic steroidal skeleton possessing a trans-diol
unit on the D ring taking advantage of high generality and stereo-
selectivity of o-quinodimethane chemistry. This compound 4 would
be a useful common starting point for divergent syntheses of A-nor
B-aromatic OSW-1 analogues and provide a versatile scaffold of SAR
studies of ring-truncated OSW-1 antitumor derivatives. Based on
these results, we are presently grappling with transformation of the
compound 4 into potentially antitumor derivatives with various
side-chains including an ether, ester, or carbonyl linkage on the C22
position, as well as biological evaluations, and the results obtained
from these efforts will be disclosed in due course.
Scheme 3. Synthesis of the substrate 5 for thermal pericyclic reaction.
The key thermal transformation of the compound 5 through the
o-quinodimethane intermediate was performed in refluxing o-di-
chlorobenzene (ca. 180 ꢁC). Gratifyingly, A-nor steroidal tricyclic
framework was efficiently constructed through the successive
pericyclic reactions in 94% yield in a highly stereoselective manner
(Scheme 4). Judging from the stereochemistry of the product 15,21
the [4þ2] cycloaddition reaction undoubtedly proceeded via the
exo transition state depicted in Fig. 2 (exo-TS1), which should be the
most stable among the possible four transition states.22 Another
exo transition state (exo-TS2), leading to the isomer 150, which
could not be detected in this reaction, would have steric repulsion
between substituent R and the o-quinodimethane moiety (Fig. 2).
Both of the MOM and TBS protecting groups in 15 could be easily
4. Experimental section
4.1. General remarks
All chemical reagents were obtained from commercial suppliers
(Aldrich, Kanto Chemical, Tokyo Chemical Industry (TCI), Wako

3984
B. Li et al. / Tetrahedron 70 (2014) 3981e3987
Pure Chemical Industries) and used without further purification.
Anhydrous solvents were obtained from commercial sources or
were prepared by distillation over the standard protocols. All
nonaqueous reactions were carried out under Ar atmosphere. Thin
layer chromatography (TLC) was performed on silica gel 60 F254
glass plates precoated with a 0.25 mm thickness of silica gel
(Merck). Column chromatography was carried out on Cica Silica Gel
(10)14 (3.3 g, 16.2 mmol), triphenylphosphine (5.1 g, 19.4 mmol),
and 2-mercaptobenzthiazol (3.25 g, 19.4 mmol) in THF (90.0 mL)
was added DIAD (3.83 mL, 19.4 mmol) at 0 ꢁC, and the mixture was
stirred for 2 h at the room temperature. The reaction mixture was
diluted with Et2O, and then the organic layer was washed with satd
NaHCO3 aq. The organic layer was dried over MgSO4 and evapo-
rated to leave a residue, which was chromatographed on silica gel
(hexane/AcOEt¼5:1) to afford (ꢀ)-2-[3-(tert-butyldimethylsilany-
loxy)-2-methylpropylsulfanyl]-benzothiazole (5.38 g, 94%) as
a colorless oil.
60N (spherical, neutral, 40e50 mm or 63e210 m
m). 1H NMR spectra
were recorded in deuterated solvents on a VARIAN Gemini 300
(300 MHz) spectrometer, or a VARIAN UNITYplus 500 (500 MHz)
spectrometer, using the residual solvent peak as an internal refer-
ence. 13C NMR spectra were recorded in deuterated solvents on
a Varian Gemini 300 (75 MHz) spectrometer. IR spectra were
measured on a JNM FT/IR-460Plus spectrometer. Mass spectra were
recorded on a JEOL D-200, JEOL JMS-GCmate II, SHIMADZU GCMS-
QP 500, or JEOL AX 505 spectrometer. The optical rotations were
determined on a JASCO DIP-1000 instrument. Melting points were
taken with a Yanagimoto micro melting point apparatus and are
uncorrected.
1H NMR (300 MHz, CDCl3):
d
7.86 (1H, ddd, J¼8.2, 1.1, 0.6 Hz),
7.74 (1H, ddd, J¼8.0,1.1, 0.6 Hz), 7.40 (1H, ddd, J¼8.2, 7.1, 1.1 Hz), 7.14
(1H, ddd, J¼8.0, 7.1, 1.1 Hz), 3.67 (1H, dd, J¼9.9, 5.2 Hz), 3.59e3.49
(2H, m), 3.24 (1H, dd, J¼13.0, 7.1 Hz), 2.17e2.11 (1H, m), 1.08 (3H, d,
J¼6.9 Hz), 0.92 (9H, s), 0.07 (6H, s); 13C NMR (75 MHz, CDCl3):
d
167.4, 153.1, 134.9, 125.7, 123.8, 121.2, 120.6, 66.3, 36.9, 35.9, 25.9,
18.3, 16.2, ꢀ5.4; MS (EI) m/z: 353 (Mþ); HRMS (EI) calcd for
C
17H27NOS2Si: 353.1303 (Mþ), found: 353.1286; ½a 2D6
ꢀ4.59 (c 1.10,
ꢂ
CHCl3).
To
a
solution of (ꢀ)-2-[3-(tert-butyldimethylsilanyloxy)-2-
4.2. Synthesis of 4, a core structure of A-nor B-aromatic OSW-
1
methylpropylsulfanyl]-benzothiazole (2.0 g, 5.66 mmol) and so-
dium periodate (3.6 g, 17.0 mmol) in CCl4 (11.0 mL), CH3CN
(11.0 mL), and H2O (22.0 mL) was added RuCl3$nH2O (0.6 mg,
4.2.1. (3-Methoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl)-acetaldehyde
2.8 mmol) at the room temperature, and the mixture was stirred for
(7). Under an Ar atmosphere, to
a
solution of 1-cyano-4-
1 h at the same temperature. The reaction mixture was extracted
with Et2O. The combined organic layers were washed with satd
NaHCO3 aq, and then with brine. The organic layer was dried over
MgSO4 and evaporated to leave a residue, which was chromato-
graphed on silica gel (hexane/AcOEt¼4:1) to afford compound 8a
(2.1 g, 95%) as a colorless oil.
methoxybenzocyclobutane (9)13 (1.60 g, 10.1 mmol) in CH2Cl2
(30.0 mL) was added dropwise DIBAL (0.95 M in hexane, 12.7 mL,
12.1 mmol) at ꢀ78 ꢁC, and the mixture was stirred for 30 min at the
same temperature. The reaction was quenched with satd NH4Cl aq,
and the mixture was stirred for 30 min at the room temperature.
The insoluble precipitate was filtered off through a Celite pad and
the filtrate was extracted with CH2Cl2. The organic layer was dried
over MgSO4 and evaporated to leave a residue, which was chro-
matographed on silica gel (hexane/AcOEt¼4:1) to afford 3-
methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde (1.59 g,
97%) as a colorless oil.
1H NMR (300 MHz, CDCl3):
d
8.21 (1H, d, J¼8.0 Hz), 8.01 (1H, d,
J¼7.7 Hz), 7.66e7.26 (2H, m), 3.83 (1H, dd, J¼14.0, 4.2 Hz), 3.64 (1H,
dd, J¼9.5, 4.2 Hz), 3.46e3.40 (1H, m), 3.33e3.25 (1H, m), 2.42e2.40
(1H, m), 1.13 (3H, d, J¼7.4 Hz), 0.82 (9H, s), 0.00 (3H, s), ꢀ0.02 (3H,
s); 13C NMR (75 MHz, CDCl3):
d 166.2, 152.4, 136.5, 127.8, 127.4,
125.2, 122.2, 66.2, 57.5, 31.6, 25.8, 18.2, 16.8, ꢀ5.4; IR (neat) 1309,
1H NMR (300 MHz, CDCl3):
d
9.67 (1H, d, J¼2.4 Hz), 7.07 (1H, d,
1144 cmꢀ1 MS (EI) m/z: 385 (Mþ); HRMS (EI) calcd for
;
J¼7.7 Hz), 6.81 (1H, dd, J¼7.7, 1.1 Hz), 6.74 (1H, d, J¼1.1 Hz),
C
17H27NO3S2Si: 385.1202 (Mþ), found: 385.1225; ½a 2D6
ꢀ7.36 (c 1.00,
ꢂ
4.17e4.13 (1H, m), 3.79 (3H, s), 3.46e3.36 (2H, m); 13C NMR
CHCl3).
(75 MHz, CDCl3): d 199.8,160.4,144.9,132.0,124.1, 114.3,108.9, 55.5,
52.9, 30.3; IR (neat) 2715, 1716, 1387 cmꢀ1; MS (EI) m/z: 162 (Mþ);
HRMS (EI) calcd for C10H10O2: 162.0680 (Mþ), found: 162.0650.
Under an Ar atmosphere, to a solution of (methoxymethyl)tri-
phenylphosphonium chloride (9.4 g, 27.4 mmol) in THF (30.0 mL)
was added dropwise phenyllithium (1.90 M in n-butyl ether,
12.2 mL, 23.2 mmol) at 0 ꢁC, and the mixture was stirred for 10 min
at the room temperature. The solution was cooled to 0 ꢁC again, and
to the above reaction mixture was added 3-methoxybicyclo[4.2.0]
octa-1,3,5-triene-7-carbaldehyde (1.5 g, 9.25 mmol), and the mix-
ture was stirred for 1 h at the same temperature. The reaction
mixture was extracted with Et2O, and then the combined organic
layers were washed with brine. The organic layer was dried over
MgSO4 and evaporated to leave a residue, which was chromato-
graphed on silica gel (hexane/AcOEt¼7:1) to afford compound 7
(1.5 g, 90%) as a colorless oil.
4.2.3. (ꢀ)-5-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropane-1-
sulfonyl]-1-phenyl-1H-tetrazole (8b). Under an Ar atmosphere, to
a
solution
of
(ꢀ)-3-(tert-butyldimethylsilanyloxy)-2-
methylpropane-1-ol (10)14 (11.0 g, 53.8 mmol), triphenylphos-
phine (16.9 g, 64.6 mmol), and 1-phenyl-1H-tetrazole-5-thiol
(11.5 g, 64.6 mmol) in THF (150.0 mL) was added DIAD (12.7 mL,
64.6 mmol) at 0 ꢁC, and the mixture was stirred for 2 h at the room
temperature. The reaction mixture was diluted with Et2O, and then
the organic layer was washed with satd NaHCO3 aq. The organic
layer was dried over MgSO4 and evaporated to leave a residue,
which was chromatographed on silica gel (hexane/AcOEt¼5:1) to
afford
sulfanyl]-1-phenyl-1H-tetrazole (15.0 g, 77%) as a colorless oil.
1H NMR (300 MHz, CDCl3):
7.59e7.53 (5H, m), 3.64 (1H, dd,
(þ)-5-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl
d
J¼10.0, 4.8 Hz), 3.55e3.47 (2H, m), 3.37 (1H, dd, J¼13.0, 6.6 Hz),
1H NMR (300 MHz, CDCl3):
d
9.88 (1H, t, J¼1.4 Hz), 7.00 (1H, d,
2.20e2.13 (1H, m), 1.05 (3H, d, J¼6.9 Hz), 0.88 (9H, s), 0.03 (6H, s);
J¼8.1 Hz), 6.75 (1H, dd, J¼8.1, 2.2 Hz), 6.68 (1H, s), 3.82e3.76 (1H,
m), 3.78 (3H, s), 3.41 (1H, dd, J¼14.0, 5.2 Hz), 2.85 (2H, dd, J¼7.7,
1.4 Hz), 2.77 (1H, dd, J¼14.0, 2.5 Hz); 13C NMR (75 MHz, CDCl3):
13C NMR (75 MHz, CDCl3):
d 154.3, 133.4, 129.6, 129.4, 123.4, 66.0,
36.7, 35.4, 25.7, 18.1, 16.0, ꢀ5.4; MS (EI) m/z: 307 (Mþꢀ57); HRMS
(EI) calcd for C13H18N4OSSi: 307.1049 (Mþꢀ57), found: 307.1046;
d
201.5, 160.0, 144.0, 139.3, 123.5, 113.7, 109.1, 55.7, 48.9, 36.2, 35.8;
½
a 2D6
To
ꢂ
þ2.59 (c 1.00, CHCl3).
IR (neat) 2721, 1721, 1387 cmꢀ1; MS (EI) m/z: 176 (Mþ); HRMS (EI)
a
solution of (þ)-5-[3-(tert-butyldimethylsilanyloxy)-2-
calcd for C11H12O2: 176.0837 (Mþ), found: 176.0851.
methylpropylsulfanyl]-1-phenyl-1H-tetrazole (2.0 g, 5.49 mmol)
and sodium periodate (3.5 g, 16.5 mmol) in CCl4 (10.0 mL), CH3CN
(10.0 mL), and H2O (20.0 mL) was added RuCl3$nH2O (0.6 mg,
4.2.2. (ꢀ)-2-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropane-1-
sulfonyl]-benzothiazole (8a). Under an Ar atmosphere, to a solution
2.8
mmol) at the room temperature, and the mixture was stirred for
of
(ꢀ)-3-(tert-butyldimethylsilanyloxy)-2-methylpropane-1-ol
5 h at the same temperature. The reaction mixture was extracted

B. Li et al. / Tetrahedron 70 (2014) 3981e3987
3985
with Et2O. The combined organic layers were washed with satd
NaHCO3 aq, and then with brine. The organic layer was dried over
MgSO4 and evaporated to leave a residue, which was chromato-
graphed on silica gel (hexane/AcOEt¼4:1) to afford compound 8b
(2.2 g, 99%) as a colorless oil.
11-stereoisomer: 1H NMR (300 MHz, CDCl3):
d
6.98 (1H, d,
J¼8.2 Hz), 6.73 (1H, dd, J¼8.2, 2.2 Hz), 6.68 (1H, d, J¼2.2 Hz),
3.85e3.57 (7H, m), 3.46e3.38 (1H, m), 3.32 (1H, dd, J¼14.0, 5.2 Hz),
3.25e2.80 (2H, br), 2.74 (1H, dd, J¼14.0, 2.5 Hz), 2.12e1.91 (2H, m),
1.83e1.71 (1H, m), 0.94e0.90 (12H, m), 0.92 (9H, s), 0.11 (6H, s); 13
C
1H NMR (300 MHz, CDCl3):
d
7.71e7.57 (5H, m), 4.05 (1H, dd,
NMR (75 MHz, CDCl3): d 159.4, 144.2, 141.0, 123.0, 113.0, 108.9, 78.7,
J¼15.0, 4.7 Hz), 3.72 (1H, dd, J¼10.0, 4.7 Hz), 3.59e3.47 (2H, m),
71.1, 67.7, 55.5, 39.6, 39.2, 37.2, 35.6, 25.9, 18.2, 14.2, ꢀ5.5; IR (neat)
2.51e2.44 (1H, m), 1.16 (3H, d, J¼6.9 Hz), 0.89 (9H, s), 0.05 (6H, s);
3454 cmꢀ1; MS (EI) m/z: 380 (Mþ); HRMS (EI) calcd for C21H36O4Si:
13C NMR (75 MHz, CDCl3):
d
154.0, 133.1, 131.5, 129.7, 125.2, 66.3,
380.2383 (Mþ), found: 380.2402; ½a 2D6
ꢀ7.65 (c 0.80, CHCl3).
ꢂ
58.7, 31.4, 26.1, 18.5, 17.1, ꢀ5.1; IR (neat) 1335, 1153 cmꢀ1; MS (EI) m/
z: 339 (Mþꢀ57); HRMS (EI) calcd for C13H19N4O3SSi: 339.0947
4.2.6. (þ)-1-(tert-Butyldimethylsilanyloxy)-5-(3-methoxybicyclo
[ 4 . 2 . 0 ] o c t a - 1 , 3 , 5 - t r i e n - 7 - y l ) - 2 - m e t h y l - 4 -
triisopropylsilanyloxypentan-3-one (12). Under an Ar atmosphere,
to a solution of compound (11) (1.5 g, 3.94 mmol) in CH2Cl2
(12.0 mL) was added 2,6-lutidine (1.37 mL, 11.8 mmol) and TIPSOTf
(1.06 mL, 3.94 mmol) at 0 ꢁC, and the mixture was stirred for 2 h at
the same temperature. The reaction mixture was diluted with
CH2Cl2, and then the organic layer was washed with brine. The
organic layer was dried over MgSO4 and evaporated to leave a res-
idue, which was chromatographed on silica gel (hexane/
AcOEt¼10:1) to afford (þ)-1-(tert-butyldimethylsilanyloxy)-5-(3-
methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)-2-methyl-4-
(Mþꢀ57), found: 339.0936; ½a 2D6
ꢀ5.22 (c 1.10, CHCl3).
ꢂ
4.2.4. (þ)-tert-Butyl-[5-(3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-
yl)-2-methylpent-3-enyloxy]-dimethylsilane (6). Under an Ar atmo-
sphere, to a solution of compound 8b (60 mg, 0.15 mmol) in toluene
(1.0 mL) was added dropwise NaHMDS (1.0 M in THF, 0.17 mL,
0.17 mmol) at ꢀ78 ꢁC, and the mixture was stirred for 30 min at the
same temperature. To the above reaction mixture was added
dropwise a solution of 18-crown-6 (40 mg, 0.15 mmol) in toluene
(1.0 mL) at ꢀ78 ꢁC, and the mixture was stirred for 30 min at the
same temperature. Then, to the reaction mixture was added
dropwise a solution of compound 7 (40 mg, 0.15 mmol) in toluene
(1.0 mL) at ꢀ78 ꢁC, and the mixture was stirred for 3 h at the same
temperature. The reaction was quenched with H2O, and the re-
action mixture was extracted with Et2O. The combined organic
layers were washed with brine. The organic layer was dried over
MgSO4 and evaporated to leave a residue, which was chromato-
graphed on silica gel (hexane/AcOEt¼20:1) to afford compound 6
(43 mg, 83%) as a colorless oil.
triisopropylsilanyloxypentan-3-ol (1.84 g, 87%) as a colorless oil.
1H NMR (300 MHz, CDCl3):
d
6.99 (1H, d, J¼7.9 Hz), 6.74 (1H, d,
J¼7.9 Hz), 6.69 (1H, s), 3.86e3.45 (5H, m), 3.78 (3H, s), 3.38e3.29
(1H, m), 2.78 (1H, d, J¼14.0 Hz), 2.16e2.00 (1H, m), 1.95e1.83 (2H,
m), 1.17e1.12 (21H, m), 1.02 (3H, d, J¼6.8 Hz), 0.91 (9H, s), 0.10 (6H,
s); 13C NMR (75 MHz, CDCl3):
d 159.4, 144.2, 140.4, 123.0, 113.1,
108.8, 73.2, 72.9, 66.3, 55.4, 39.4, 38.5, 36.4, 31.7, 26.0, 22.8, 18.3,
14.2, 13.1, ꢀ5.3; IR (neat) 3545 cmꢀ1; MS (EI) m/z: 536 (Mþ); HRMS
1H NMR (300 MHz, CDCl3):
d
6.98 (1H, dd, J¼8.0 2.7 Hz),
(EI) calcd for C30H56O4Si2: 536.3717 (Mþ), found: 536.3703; ½a 2D6
ꢂ
6.74e6.68 (2H, m), 5.56 (1H, dt, J¼15.0, 6.3 Hz), 5.42 (1H, dd, J¼15.0,
2.2 Hz), 3.77 (3H, s), 3.53e3.47 (1H, m), 3.43e3.36 (2H, m), 3.24
(1H, dd, J¼14.0, 5.0 Hz), 2.71 (1H, dd, J¼14.0, 2.5 Hz), 2.37e2.27 (3H,
m), 1.00 (3H, d, J¼6.7 Hz), 0.90 (9H, s), 0.05 (6H, s); 13C NMR
þ2.08 (c 0.75, CHCl3).
Under an Ar atmosphere, to a solution of (þ)-1-(tert-butyldi-
methylsilanyloxy)-5-(3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-
yl)-2-methyl-4-triisopropylsilanyloxypentan-3-ol
(326
mg,
(75 MHz, CDCl3):
d
159.4, 144.2, 141.0, 134.2, 127.8, 122.9, 112.9,
0.61 mmol) in CH2Cl2 (6.0 mL) was added MS4A (300 mg), NMO
(213 mg, 1.82 mmol), and TPAP (43 mg, 0.12 mmol) at the room
temperature, and the mixture was stirred for 2 h at the same
temperature. The insoluble precipitate was filtered off through
a Celite pad and evaporated to leave a residue, which was chro-
matographed on silica gel (hexane/AcOEt¼20:1) to afford com-
pound 12 (306 mg, 95%) as a colorless oil.
108.9, 68.3, 55.4, 42.0, 39.6, 37.9, 35.2, 26.0, 18.5, 16.9, ꢀ5.1; IR
(neat) 1589, 1025 cmꢀ1; MS (EI) m/z: 346 (Mþ); HRMS (EI) calcd for
C
21H34O2Si: 346.2328 (Mþ), found: 346.2336; ½a 2D5
þ0.29 (c 1.30,
ꢂ
CHCl3).
4.2.5. (ꢀ)-5-(tert-Butyldimethylsilanyloxy)-1-(3-methoxybicyclo
[4.2.0]octa-1,3,5-trien-7-yl)-4-methylpentane-2,3-diol (11). A mix-
ture of methanesulfonamide (549 mg, 5.8 mmol), AD-mix-
1H NMR (300 MHz, CDCl3):
d 7.02e6.92 (1H, m), 6.76e6.71 (1H,
m), 6.67 (1H, s), 4.55e4.40 (1H, m), 3.90e3.83 (1H, m), 3.77 (3H, s),
3.67e3.46 (2H, m), 3.33e3.26 (1H, m), 3.21e3.13 (1H, m),
2.80e2.70 (1H, m), 2.26e1.93 (2H, m), 1.20e1.01 (24H, m), 0.91 (9H,
a
(8.1 g) in t-BuOH (30 mL), and H2O (30 mL) was stirred at 0 ꢁC
for 15 min. Compound 6 (2.0 g, 5.8 mmol) was added to the
solution at 0 ꢁC, and the mixture was stirred for 24 h at the same
temperature. Then, sodium hydrogen sulfite (8.0 g) was added to
the solution at 0 ꢁC, and the mixture was stirred for 1 h at the
room temperature. The reaction mixture was extracted with
AcOEt. The combined organic layers were washed with satd 2 N
KOH aq, and then with brine. The organic layer was dried over
MgSO4 and evaporated to leave a residue, which was chroma-
tographed on silica gel (hexane/AcOEt¼4:1) to afford compound
11 (1.8 g, 82%) as a colorless oil and 11-stereoisomer (220 mg,
10%) as a colorless oil.
s), 0.01 (6H, s); 13C NMR (75 MHz, CDCl3):
d 213.5, 159.5, 143.9,
140.2, 123.0, 113.1, 108.9, 78.0, 64.7, 55.4, 43.9, 39.5, 38.7, 36.0, 31.6,
25.9, 18.2, 14.4, 12.8, ꢀ5.4; IR (neat) 1715 cmꢀ1; MS (EI) m/z: 534
(Mþ); HRMS (EI) calcd for C30H54O4Si2: 534.3561 (Mþ), found:
534.3572; ½a 2D5
þ17.62 (c 1.32, CHCl3).
ꢂ
4.2.7. (þ)-1-(tert-Butyldimethylsilanyloxy)-4-hydroxy-5-(3-
methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)-2-methylpentan-3-one
(13). Under an Ar atmosphere, to a solution of compound 12
(264 mg, 0.50 mmol) in THF (3.0 mL) was added dropwise TBAF
(1 M in THF, 1.50 mL, 1.50 mmol) at the room temperature, and the
mixture was stirred for 3 h at the same temperature. The reaction
was quenched with satd NH4Cl aq, and the reaction mixture was
extracted with AcOEt. The organic layer was dried over MgSO4 and
evaporated to leave a residue, which was chromatographed on
silica gel (hexane/AcOEt¼2:3) to afford (þ)-1,4-dihydroxy-5-(3-
methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)-2-methylpentan-3-
one (114 mg, 87%) as a colorless oil.
1H NMR (300 MHz, CDCl3):
d 7.02e6.98 (1H, m), 6.73 (1H, dd,
J¼8.0, 2.2 Hz), 6.69 (1H, d, J¼2.2 Hz), 3.93e3.87 (1H, m), 3.81 (1H,
dd, J¼10.0, 2.9 Hz), 3.77 (3H, s), 3.70e3.52 (3H, m), 3.36e3.29 (1H,
m), 3.10e2.95 (2H, br), 2.74 (1H, dd, J¼14.0, 2.5 Hz), 2.04e1.91 (1H,
m), 1.87e1.66 (2H, m), 0.99e0.88 (3H, m), 0.89 (9H, s), 0.10 (6H, s);
13C NMR (75 MHz, CDCl3):
d 159.2, 144.0, 140.7, 122.7, 112.8, 108.7,
78.4, 70.4, 66.2, 55.2, 39.3, 38.2, 37.8, 35.5, 25.8, 18.1, 11.6, ꢀ5.6; IR
(neat) 3414 cmꢀ1; MS (EI) m/z: 380 (Mþ); HRMS (EI) calcd for
C
21H36O4Si: 380.2383 (Mþ), found: 380.2419; ½a 2D6
ꢂ
ꢀ14.00 (c 1.10,
1H NMR (300 MHz, CDCl3):
8.0 Hz), 6.72e6.65 (2H, m), 4.44e4.32 (1H, m), 4.11e3.56 (6H, m),
d
7.02 and 6.95 (1H, d, J¼8.2 and
CHCl3).

3986
B. Li et al. / Tetrahedron 70 (2014) 3981e3987
3.29 (1H, d, J¼14.0, 5.2 Hz), 3.15e2.98 (1H, m), 2.80e2.70 (1H, m),
2.06e1.74 (2H, m), 1.01 and 0.98 (3H, d, J¼7.4 and 7.2 Hz); 13C NMR
NMR (75 MHz, CDCl3): d 159.3,145.7, 144.2,141.2, 122.7, 112.9, 108.9,
97.7, 97.2, 82.5, 81.3, 65.9, 56.0, 55.4, 40.3, 36.3, 36.0, 35.5, 25.9, 20.7,
18.2, 12.7, ꢀ5.6; IR (neat) 3458, 1588 cmꢀ1; MS (EI) m/z: 464 (Mþ);
HRMS (EI) calcd for C26H44O5Si: 464.2958 (Mþ), found: 464.2950;
(75 MHz, CDCl3): d 215.7, 159.5, 144.1, 139.8, 123.1, 113.1, 108.9, 75.0,
64.0, 55.4, 43.4, 39.2, 38.1, 35.6, 13.7; IR (neat) 3445, 1709 cmꢀ1; MS
(EI) m/z: 246 (Mþ); HRMS (EI) calcd for C15H20O4: 264.1362 (Mþ),
½
a 2D6
ꢂ
ꢀ18.0 (c 1.35, CHCl3).
found: 264.1336; ½a D26
þ35.41 (c 1.35, CHCl3).
ꢂ
Under an Ar atmosphere, to a solution of (þ)-1.4-dihydroxy-5-
(3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)-2-methylpentan-3-
one (98 mg, 0.37 mmol) in DMF (3.0 mL) was added imidazole
(51 mg, 0.41 mmol) and TBSCl (62 mg, 0.41 mmol) at 0 ꢁC, and the
mixture was stirred for 2 h at the room temperature. The reaction
mixture was diluted with H2O, and was extracted with Et2O. The
organic layer was dried over MgSO4 and evaporated to leave a res-
idue, which was chromatographed on silica gel (hexane/
AcOEt¼2:1) to afford compound 13 (140 mg, quant.) as a colorless
oil.
4.2.10. (þ)-3-[2-(tert-Butyldimethylsilanyloxy)-1-methylethyl]-7-
methoxy-2-methoxymethoxy-3a-methyl-2,3,3a,4,5,9b-hexahydro-
1H-cyclopenta[a]naphthalene-3-ol (15). Under an Ar atmosphere,
compound
5 (80 mg, 0.17 mmol) was dissolved in o-di-
chlorobenzene (10.0 mL), and the solution was refluxed on a heat-
ing oil bath for 7 h. Then, the solvent was evaporated off under
a reduced pressure. The residue was chromatographed on silica gel
(hexane/AcOEt¼7:1) to afford compound 15 (75 mg, 94%) as a col-
orless oil.
1H NMR (500 MHz, CDCl3):
d
6.71 (1H, dd, J¼8.5, 1.2 Hz),
1H NMR (300 MHz, CDCl3):
d
7.05 and 6.99 (1H, d, J¼7.9 Hz),
6.71e6.67 (2H, m), 4.74 (1H, d, J¼6.5 Hz), 4.65 (1H, d, J¼6.5 Hz), 4.32
(1H, dd, J¼9.8, 1.7 Hz), 4.13 (1H, dd, J¼7.7, 3.8 Hz), 3.78 (3H, s), 3.63
(1H, dd, J¼9.8, 2.5 Hz), 3.41 (3H, s), 3.21 (1H, dd, J¼12.0, 8.1 Hz), 2.81
(2H, t, J¼7.7 Hz), 2.74 (4H, m), 2.78e2.68 (1H, m), 2.38e2.32 (1H,
m), 2.20e2.16 (1H, m), 1.68e1.62 (1H, m), 1.60e1.54 (2H, m), 1.16
6.77e6.68 (2H, m), 4.38 and 4.28 (1H, dd, J¼9.6, 3.1 and 9.4, 3.3 Hz),
3.83e3.53 (6H, m), 3.34 (1H, dd, J¼14.0, 5.2 Hz), 3.23e3.11 (1H, m),
2.85e2.73 (1H, m), 2.18e2.05 (2H, m), 1.92e1.75 (1H, m), 1.07e1.00
(3H, m), 0.86 and 0.85 (9H, s), 0.03e0.02 (6H, s); 13C NMR (75 MHz,
CDCl3):
d
215.3, 159.5, 144.3, 140.2, 123.2, 113.1, 108.8, 75.7, 65.5,
(3H, d, J¼7.3 Hz), 0.93 (9H, m), 0.59 (3H, s), 0.11 and 0.10 (6H, s); 13
C
55.4, 43.6, 39.4, 38.2, 35.9, 25.9, 18.3, 13.7, ꢀ5.5; IR (neat) 3481,
NMR (75 MHz, CDCl3): d 157.2, 138.2, 133.1, 125.7, 113.0, 110.4, 96.3,
1713 cmꢀ1; MS (EI) m/z: 378 (Mþ); HRMS (EI) calcd for C21H34O4Si:
87.5, 87.0, 68.8, 56.5, 55.1, 47.4, 43.0, 34.2, 32.6, 30.0, 27.8, 25.9, 18.2,
378.2226 (Mþ), found: 378.2252; ½a 2D6
ꢂ
þ12.97 (c 1.40, CHCl3).
14.9, 13.4, ꢀ5.6; IR (neat) 3455 cmꢀ1; MS (EI) m/z: 464 (Mþ); HRMS
(EI) calcd for C26H44O5Si: 464.2958 (Mþ), found: 464.2986; ½a 2D6
ꢂ
4.2.8. (ꢀ)-1-(tert-Butyldimethylsilanyloxy)-5-(3-methoxybicyclo
[4.2.0]octa-1,3,5-trien-7-yl)-4-methoxymethoxy-2-methylpentan-3-
one (14). Under an Ar atmosphere, to a solution of compound 13
(171 mg, 0.45 mmol) in CH2Cl2 (3.0 mL) was added diisopropyle-
þ47.36 (c 1.05, CHCl3).
4.2.11. (þ)-3-(2-Hydroxy-1-methylethyl)-7-methoxy-3a-methyl-
2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-2,3-diol
(16). Under an Ar atmosphere, to a solution of compound 15
(656 mg, 1.41 mmol) in CH2Cl2 (2.0 mL) was added thiophenol
(1.45 mL, 14.1 mmol) and BF3$Et2O (0.72 mL, 5.65 mmol) at 0 ꢁC,
and the mixture was stirred for 12 h at the room temperature. The
reaction was diluted with AcOEt, and then the organic layer was
washed with 5% NaOH aq, and then with brine. The organic layer
was dried over MgSO4 and evaporated to leave a residue, which was
chromatographed on silica gel (hexane/AcOEt¼1:2) to afford
compound 16 (427 mg, 99%) as a colorless crystal.
thylamine (348 mL, 2.0 mmol) and MOMCl (103 mL, 1.35 mmol) at
0 ꢁC, and the mixture was stirred for 20 h at the room temperature.
The reaction mixture was diluted with CH2Cl2, and then the organic
layer was washed with 10% HCl aq, satd NaHCO3 aq and brine,
successively. The organic layer was dried over MgSO4 and evapo-
rated to leave a residue, which was chromatographed on silica gel
(hexane/AcOEt¼3:1) to afford 14 (159 mg, 84%) as a colorless oil.
1H NMR (300 MHz, CDCl3):
d
7.08 and 6.97 (1H, d, J¼7.9 Hz),
6.77e6.68 (2H, m), 4.73e4.60 (2H, m), 4.43 and 4.27 (1H, dd, J¼9.6,
3.0 and 8.7, 4.3 Hz), 3.88e3.80 (1H, m), 3.78 and 3.77 (3H, s),
3.65e3.58 (1H, m), 3.53e3.46 (1H, m), 3.41 and 3.38 (3H, s),
3.38e3.28 (1H, m), 3.09e2.97 (1H, m), 2.12e1.89 (2H, m), 1.03 and
1.01 (3H, d, J¼7.0 and 7.0 Hz), 0.83 and 0.82 (9H, s), 0.01 and 0.00
1H NMR (500 MHz, CDCl3):
d
6.96 (1H, d, J¼8.1 Hz), 6.72e6.68
(2H, m), 4.22 (1H, dd, J¼7.5, 5.0 Hz), 3.93e3.82 (1H, dd, J¼18.0,
10.0 Hz), 3.78 (3H, s), 3.73 (1H, dd, J¼10.0, 3.5 Hz), 3.14 (1H, dd,
J¼12.5, 7.5 Hz), 2.92e2.78 (2H, m), 2.74 (1H, ddd, J¼12.5, 7.5,
7.5 Hz), 2.56e2.46 (1H, m), 2.40e1.50 (3H, br), 2.08 (1H, ddd,
J¼12.5, 8.5, 8.5 Hz), 1.74e1.60 (2H, m), 1.00 (3H, d, J¼7.0 Hz), 0.73
(6H, s); 13C NMR (75 MHz, CDCl3):
d 212.7, 159.6, 143.8, 139.9, 123.0,
113.2, 108.8, 96.0, 80.3, 64.8, 56.0, 55.4, 45.0, 39.3, 35.7, 35.3, 25.9,
18.3, 13.8, ꢀ5.4,; IR (neat) 1729 cmꢀ1; MS (EI) m/z: 422 (Mþ); HRMS
(3H, s); 13C NMR (75 MHz, CDCl3):
d 157.2, 137.5, 132.5, 126.2, 113.1,
(EI) calcd for C23H38O5Si: 422.2489 (Mþ), found: 422.2498; ½a 2D6
ꢂ
110.8, 85.8, 81.8, 66.1, 55.2, 47.9, 43.4, 35.6, 34.0, 30.4, 27.6, 14.5,
ꢀ9.58 (c 0.90, CHCl3).
12.7; IR (neat) 3376 cmꢀ1; MS (EI) m/z: 306 (Mþ); HRMS (EI) calcd
for C18H26O4: 306.1831 (Mþ), found: 306.1825; ½a 2D5
þ80.20 (c 0.26,
ꢂ
4.2.9. (ꢀ)-3-[2-(tert-Butyldimethylsilanyloxy)-1-methylethyl]-5-(3-
methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)-4-methoxymethoxy-2-
methylpent-1-en-3-ol (5). Under an Ar atmosphere, to a solution of
compound 14 (90 mg, 0.21 mmol) in THF (10.0 mL) was added
CHCl3); mp 191e193 ꢁC.
4.2.12. (þ)-2-(tert-Butyldimethylsilanyloxy)-3-(2-hydroxy-1-
methylethyl)-7-methoxy-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-cy-
clopenta[a]naphthalene-3-ol (4). Compound 16 (37 mg, 0.12 mmol)
in CH2Cl2 (2.0 mL) was added 2,6-lutidine (0.11 mL, 0.97 mmol) and
TBSOTf (0.14 mL, 0.60 mmol) at 0 ꢁC, and the mixture was stirred for
6 h at the same temperature. The reaction mixture was diluted with
CH2Cl2, and then the organic layer was washed with brine. The
organic layer was dried over MgSO4 and evaporated to leave a res-
idue, which was chromatographed on silica gel (hexane/
AcOEt¼6:1) to afford (þ)-3-[2-(tert-butyldimethylsilanyloxy)-1-
methylethyl]-7-methoxy-2-tert-butyldimethylsilanyloxy-3a-
methyl-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-
ol (65 mg, quant.) as a colorless oil.
isopropenyl magnesium bromide (0.50
M in THF, 1.9 mL,
0.96 mmol) at ꢀ78 ꢁC, and the mixture was stirred for 19 h at the
same temperature. The reaction was quenched with satd NH4Cl aq.
The reaction mixture was extracted with Et2O, and then the organic
layer was washed with brine. The organic layer was dried over
MgSO4 and evaporated to leave a residue, which was chromato-
graphed on silica gel (hexane/AcOEt¼7:1) to afford compound 5
(91 mg, 91%) as a colorless oil.
1H NMR (300 MHz, CDCl3):
d 7.04e7.00 (1H, m), 6.74e6.69 (2H,
m), 5.12 (1H, d, J¼2.5 Hz), 4.99 (1H, d, J¼2.5 Hz), 4.84e4.69 (2H, m),
4.39e4.31 (2H, m), 3.92e3.63 (2H, m), 3.77 (3H, s), 3.43e3.22 (1H,
m), 3.39 (3H, s), 2.78e2.68 (1H, m), 2.26e2.20 (1H, m), 1.92e1.77
(1H, m), 1.85 (3H, s), 1.29e0.87 (12H, m), 0.15e0.12 (3H, m); 13C
1H NMR (300 MHz, CDCl3):
m), 4.68e4.60 (1H, m), 4.34e4.26 (2H, m), 3.78 (3H, s), 3.59 (1H, dd,
d 6.95e6.91 (1H, m), 6.72e6.68 (2H,

B. Li et al. / Tetrahedron 70 (2014) 3981e3987
3987
3. (a) Sugimoto, K.; Tamura, K.; Ohta, N.; Tohda, C.; Toyooka, N.; Nemoto, H.;
Matsuya, Y. Bioorg. Med. Chem. Lett. 2012, 22, 449; (b) Matsuya, Y.; Suzuki, N.;
Kobayashi, S.; Miyahara, T.; Ochiai, H.; Nemoto, H. Bioorg. Med. Chem. 2010, 18,
1477; (c) Matsuya, Y.; Katayanagi, H.; Ohdaira, T.; Wei, Z.-L.; Kondo, T.; Nemoto,
H. Org. Lett. 2009, 11, 1361; (d) Matsuya, Y.; Imamura, Y.; Miyahara, T.; Ochiai,
H.; Nemoto, H. Eur. J. Org. Chem. 2008, 1426; (e) Matsuya, Y.; Ohsawa, N.;
Nemoto, H. J. Am. Chem. Soc. 2006, 128, 13072; (f) Matsuya, Y.; Ohsawa, N.;
Nemoto, H. J. Am. Chem. Soc. 2006, 128, 412; (g) Matsuya, Y.; Sasaki, K.; Nagaoka,
M.; Kakuda, H.; Toyooka, N.; Imanishi, N.; Ochiai, H.; Nemoto, H. J. Org. Chem.
2004, 69, 7989.
4. (a) Matsuya, Y.; Itoh, T.; Nemoto, H. Eur. J. Org. Chem. 2003, 2221; (b) Matsuya, Y.;
Masuda, S.; Itoh, T.; Murai, T.; Nemoto, H. J. Org. Chem. 2005, 70, 6898.
5. (a) Hu, Y.; Zorumski, C. F.; Covey, D. F. J. Org. Chem. 1995, 60, 3619; (b) Zeng, C.;
Han, M.; Covey, D. F. J. Org. Chem. 2000, 65, 2264.
6. (a) Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.; Nikaido, T.; Ohmoto, T. Phyto-
chemistry 1992, 31, 3969; (b) Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.;
Hirano, T.; Oka, K.; Maekawa, R.; Wada, T.; Sugita, K.; Beutler, J. A. Bioorg. Med.
Chem. Lett. 1997, 7, 633.
J¼10.0, 2.7 Hz), 3.21e3.15 (1H, m), 2.84e2.79 (2H, m), 2.74e2.64
(1H, m), 2.37e2.21 (2H, m), 1.63e1.53 (2H, m), 1.16 (3H, d, J¼7.1 Hz),
0.94 (9H, s), 0.88 (9H, s), 0.63 (3H, s), 0.12e0.03 (12H, m); 13C NMR
(75 MHz, CDCl3):
d 157.3, 138.3, 133.3, 125.7, 113.1, 110.4, 87.5, 82.5,
68.9, 55.2, 47.3, 43.0, 36.1, 34.0, 30.2, 27.8, 25.9, 25.8, 18.2, 17.8, 14.8,
13.4, ꢀ2.8, ꢀ5.4; IR (neat) 3477 cmꢀ1; MS (EI) m/z: 516 (Mþꢀ18);
½
a 2D5
To
ꢂ
þ46.10 (c 0.23, CHCl3).
a
solution of (þ)-3-[2-(tert-butyldimethylsilanyloxy)-1-
methylethyl]-7-methoxy-2-tert-butyldimethylsilanyloxy-3a-
methyl-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-
ol (59 mg, 0.11 mmol) in THF (0.6 mL) and H2O (0.6 mL) was added
dropwise AcOH (1.8 mL) at the room temperature, and the mixture
was stirred for 9 h at the same temperature. To the resulting so-
lution was added satd NH4Cl aq. The reaction mixture was extrac-
ted with AcOEt, and then the organic layer was washed with satd
NH4Cl aq. The organic layer was dried over MgSO4 and evaporated
to leave a residue, which was chromatographed on silica gel
(hexane/AcOEt¼1:1) to afford compound 4 (42 mg, 91%) as a col-
orless oil.
7. (a) Matsuya, Y.; Masuda, S.; Ohsawa, N.; Adam, S.; Tschamber, T.; Eustache, J.;
Kamoshita, K.; Sukenaga, Y.; Nemoto, H. Eur. J. Org. Chem. 2005, 803; (b)
Tschamber, T.; Adam, S.; Matsuya, Y.; Masuda, S.; Ohsawa, N.; Maruyama, S.;
Kamoshita, K.; Nemoto, H.; Eustache, J. Bioorg. Med. Chem. Lett. 2007, 17, 5101.
8. Minato, D.; Li, B.; Zhou, D.; Shigeta, Y.; Toyooka, N.; Sakurai, H.; Sugimoto, K.;
Matsuya, Y. Tetrahedron 2013, 69, 8019.
9. It has been reported that 22-deoxo-, 23-oxa-, and 22-deoxo-23-oxa-OSW-1
analogues exhibit potent antitumor activity comparable with natural OSW-1;
see: (a) Deng, L.; Wu, H.; Yu, B.; Jiang, M.; Wu, J. Bioorg. Med. Chem. Lett.
2004, 14, 2781; (b) Shi, B.; Wu, H.; Yu, B.; Wu, J. Angew. Chem., Int. Ed. 2004, 43,
4324; (c) Qin, H.-J.; Tian, W.-S.; Lin, C.-W. Tetrahedron Lett. 2006, 47, 3217; (d)
Wojtkielewicz, A.; Dlugosz, M.; Maj, J.; Morzycki, J. W.; Nowakowski, M.; Re-
nkiewicz, J.; Strnad, M.; Swaczynova, J.; Wilczewska, A. Z.; Wojcik, J. J. Med.
Chem. 2007, 50, 3667; (e) Maj, J.; Morzycki, J. W.; Rarova, L.; Oklestkova, J.;
Strnad, M.; Wojtkielewicz, A. J. Med. Chem. 2011, 54, 3298; (f) Zheng, D.; Guan,
Y.; Chen, X.; Xu, Y.; Chen, X.; Lei, P. Bioorg. Med. Chem. Lett. 2011, 21, 3257.
10. Kolb, H.; Van Niewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
11. For recent review, see: (a) Blakemorea, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563; (b) Chatterjee, B.; Bera, S.; Mondal, D. Tetrahedron: Asymmetry 2014, 25, 1.
12. Nemoto, H.; Nagai, M.; Fukumoto, K.; Kametani, T. J. Org. Chem. 1985, 50, 2764.
13. Kametani, T.; Kato, Y.; Honda, T.; Fukumoto, K. J. Am. Chem. Soc. 1976, 98, 8185.
14. Martin, S. F.; Colapret, J. A.; Dappen, M. S.; Dupre, B.; Murphy, C. J. J. Org. Chem.
1989, 54, 2209.
1H NMR (300 MHz, CDCl3):
d
6.92 (1H, d, J¼8.5 Hz), 6.72e6.69
(2H, m), 4.29 (1H, dd, J¼7.7, 4.4 Hz), 4.17 (1H, dd, J¼11.0, 2.5 Hz),
3.78 (3H, s), 3.67 (1H, dd, J¼11.0, 3.3 Hz), 3.17e3.11 (1H, m),
2.86e2.81 (2H, m), 2.69 (1H, dt, J¼14.0, 7.7 Hz), 2.31e2.13 (2H, m),
2.05e1.90 (2H, br), 1.70e1.50 (2H, m), 1.19 (3H, d, J¼7.4 Hz), 0.86
(9H, s), 0.67 (3H, s), 0.15 and 0.13 (6H, s); 13C NMR (75 MHz, CDCl3):
d
157.3, 137.8, 132.8, 126.0, 113.2, 110.7, 88.1, 81.7, 67.9, 55.2, 47.3,
43.1, 36.1, 34.6, 30.2, 27.6, 25.9, 17.8, 14.4, 12.7, ꢀ3.2, ꢀ5.4; IR (neat)
3432 cmꢀ1; MS (EI) m/z: 420 (Mþ); HRMS (EI) calcd for C24H40O4Si:
420.2696 (Mþ), found: 420.2722; ½a 2D6
þ52.80 (c 1.19, CHCl3).
ꢂ
Acknowledgements
15. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26.
16. (a) Pospisil, J. Tetrahedron Lett. 2011, 52, 2348; (b) Billard, F.; Robiette, R.;
Pospisil, J. J. Org. Chem. 2012, 77, 6358.
17. Although the combination of NaHMDS/18-crown-6 was reported not to be so
effective (Ref. 16a), this combination brought good effect in our present reaction
system.
This work was supported in part by a Grant-in-Aid (No.
15390004) for Scientific Research by the Ministry of Education,
Culture, Sports, Science, and Technology of the Japanese
Government.
18. Because we used racemic aldehyde 7, the compound 6 (as well as 5 and 11e14)
was a mixture of two diastereomers due to a chiral center on the cyclobutene
ring. These isomers could not be distinguished in the 1H NMR spectra.
19. A small amount of another diastereomer was also obtained (10%). Absolute
configuration of the diol was presumed from the empirical model.
20. Relative configuration of the tertiary hydroxyl group was confirmed based on
an NOE experiment after conversion to the compound 16 having a rigid tri-
cyclic system. Details are described in Supplementary data.
Supplementary data
NMR charts for all new compounds and stereostructure de-
termination data are available. Supplementary data related to this
article can be found at http://dx.doi.org/10.1016/j.tet.2014.04.079.
21. The observed stereochemistry of the stereogenic centers on the D ring was
supported by good similarity of 1H NMR spectra of the compound 16 with that
of A-nor B-aromatic OSW-1 aglycone with the same tricyclic framework and
trans-diol unit, reported by our group (Ref. 4a).
22. The two endo transition states, leading to cis-fused cycloadducts, should have
a severe steric repulsion between the aromatic ring and the alkyl chain.
References and notes
1. (a) Sadana, A. K.; Saini, R. K.; Billups, W. E. Chem. Rev. 2003, 103, 1539; (b)
Segura, J. L.; Martin, N. Chem. Rev. 1999, 99, 3199; (c) Oppolzer, W. Synthesis
1978, 793.
2. Nemoto, H.; Fukumoto, K. Tetrahedron 1998, 54, 5425 and references cited
therein.