A practical asymmetric synthesis of trans-4,5-benzhydrindan-1-ones as a precursor of A-nor B-aromatic steroidal compounds

Article abstract of DOI:10.1021/jo051060w

The enantio-controlled synthesis of trans-4,5-benzhydrindan-1-ones was achieved by means of a stereoselective [4+2] cycloaddition of o-quinodimethanes generated by a thermal cleavage of benzocyclobutene derivatives as a key step. The chiral substrates of

Full text of DOI:10.1021/jo051060w

A Practical Asymmetric Synthesis of
trans-4,5-Benzhydrindan-1-ones as a Precursor of A-Nor
B-Aromatic Steroidal Compounds
Yuji Matsuya, Seiji Masuda, Takakatsu Itoh, Taiki Murai, and Hideo Nemoto*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani,
Toyama 930-0194, Japan
nemotoh@ms.toyama-mpu.ac.jp
Received May 27, 2005
The enantio-controlled synthesis of trans-4,5-benzhydrindan-1-ones was achieved by means of a
stereoselective [4+2] cycloaddition of o-quinodimethanes generated by a thermal cleavage of
benzocyclobutene derivatives as a key step. The chiral substrates of the thermal reaction were
synthesized by a diastereoselective Grignard addition to the chiral O-isopropylideneglyceroketones
connected to a benzocyclobutene ring, which were simply prepared from D-mannitol as a chiral
source. This approach can provide a new efficient access to A-nor B-aromatic steroidal compounds.
Introduction
succeeded in sharply saving the number of overall steps
to increase the efficiency and the practicality of the
method. In this paper, we describe a detailed account of
this synthetic study.
trans-4,5-Benzhydrindan-1-ones consist of an A-nor
B-aromatic steroidal skeleton, which are key intermedi-
ates for the synthesis of biologically important steroid-
like compounds.1 A difficulty in constructing the trans-
fused C,D-ring system, however, has restricted available
synthetic methods to a few reported examples, especially
in an enantioselective fashion.2 In a recent communica-
tion,3 we have reported the synthesis of an optically active
trans-4,5-benzhydrindan-1-one derivative based on the
o-quinodimethane chemistry and its utility for the syn-
thesis of a modified aglycon part of OSW-1, potent
antitumor steroid saponin.4 Although this preliminary
study provided a new efficient approach to such a tricyclic
system, it left some room for improvment for practical
and large-quantity synthesis. In this context, we have
Results and Discussion
Our continuous research on the o-quinodimethane
chemistry using thermal cleavage of benzocyclobutene
derivatives has revealed that subsequent intramolecular
[4+2] cycloaddition works well for constructing the
steroidal and steroid-like skeletons with high generality
and stereoselectivity, including formation of the C,D-ring
system having a trans relative configuration.1 However,
our previous studies for enantioselective synthesis of
trans-4,5-benzhydrindans employing several chiral sub-
strates ended in disappointing results, although satisfac-
tory trans stereoselectivity was observed.2b,c To achieve
an efficient and practical synthesis of optically active
A-nor steroidal compounds, we designed new chiral
substrates 3 possessing a dimethyl-1,3-dioxolane moiety,
whose bulkiness would restrict the transition state of the
cycloaddition to an exo-type one (leading to the trans
stereochemistry) concomitant with the desired facial
selectivity (Scheme 1). We planned to synthesize sub-
strates 3 from chiral ketones 2 via a 1,2-asymmetric
induction process. The key stages for this strategy are
(1) preparation of compounds 2 from readily available
benzocyclobutene 1,5 (2) diastereoselective nucleophilic
(1) Nemoto, H.; Fukumoto, K. Tetrahedron 1998, 54, 5425-5464 and
references therein.
(2) (a) Ravindranathan, T.; Chavan, S. P.; Patil, S. S.; Pai, G.
Tetrahedron Lett. 2002, 43, 1889-1891. (b) Nemoto, H.; Nagai, M.;
Kohzuki, K.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1988, 2835-
2838. (c) Nemoto, H.; Matsuhashi, N.; Satoh, A.; Fukumoto, K. J. Chem.
Soc., Perkin Trans. 1 1992, 495-498. For classical synthesis of the
racemates see: (d) Bachmann, W. E.; Thomas, D. G. J. Am. Chem.
Soc. 1942, 64, 94-97. For a successful enantioselective synthesis see:
(e) Bondon, D.; Pietrasanta, Y.; Pucci, B. J. Chem. Res. (S) 1980, 112-
113.
(3) Matsuya, Y.; Itoh, T.; Nemoto, H. Eur. J. Org. Chem. 2003,
2221-2224.
(4) Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.; Nikaido, T.;
Ohmoto, T. Phytochemistry 1992, 31, 3969-3973.
10.1021/jo051060w CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/23/2005
6898
J. Org. Chem. 2005, 70, 6898-6903

Synthesis of trans-4,5-Benzhydrindan-1-ones
SCHEME 1
SCHEME 3a
a Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, Et3N;
(b) K2CO3, MeOH; (c) MeOC(dCH2)Me, PPTS, CH2Cl2 (25% in 3
steps).
dihydroxylation with (DHQD)2AQN proceeded success-
fully, subsequent acetonization of the resulting triol 8,
unfortunately, provided only 22% yield of the desired
acetonide 9, and one of several other products was
determined as a five-membered cyclic acetal isomer.8
Consequently we directed our attention to the Sharp-
less asymmetric epoxidation of the allylic alcohol, because
a promising method for converting epoxy alcohols to five-
membered cyclic carbonates had been reported.9 This
approach has already been described in our previous
communication,3 and briefly shown in Scheme 3. To
transform compound 10 (95% ee)10 to the target chiral
ketone 2a, we first tried a simple three-step transforma-
tion including Swern oxidation, alkaline carbonate cleav-
age, and acetonization. Although this provided the ketone
2a in moderate yields, it was found that this transforma-
tion involved considerable loss of the optical purity,
probably due to the susceptibility of the intermediary
keto-carbonate under basic conditions.11 Thus, we were
compelled to employ a rather circuitous pathway (5
steps), namely, protection of the alcohol 10 as a silyl
ether, reductive cleavage of the cyclic carbonate, aceton-
ization of the resulting diol, desilylation, and TPAP
oxidation.3 This sequential transformation provided the
target ketone 2a, the optical purity of which was pre-
served completely.12
SCHEME 2a
a Reagents and conditions: (a) LDA, THF, Br(CH2)3OTHP
(81%); (b) HCl, H2O, MeOH; (c) (COCl)2, DMSO, CH2Cl2, Et3N;
(d) NaH, (EtO)2P(dO)CH2CO2Et, THF (42% in 3 steps); (e) DIBAL,
Et2O (63%); (f) (DHQD)2AQN, t-BuOH, H2O (87%); (g) MeOC-
(dCH2)Me, HCl, DMF (22%).
Although the study mentioned above brought about a
successful synthesis of the chiral ketone 2a, we explored
a more efficient and fewer step approach for the com-
pounds. In a new plan, the chiral dimethyldioxolane
subunit of 2 can be directly installed by using (R)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde, which is readily
prepared from an inexpensive natural chiral source,
D-mannitol.13 As shown in Scheme 4, the cyano group in
the starting benzocyclobutene 1a was converted to the
addition to 2, and (3) stereoselective pericyclic reaction
of 3 and subsequent oxidative degradation.
1. Preparation of Chiral Ketones 2. For the con-
struction of a chiral center of compound 2, Sharpless
asymmetric dihydroxylation was first applied as shown
in Scheme 2. 4-Methoxybenzocyclobutene-1-carbonitrile
(1a)5 was alkylated and subsequently deprotected in
accordance with the reported procedure6 to afford the
alcohol, which was transformed into the homologated
allylic alcohol 7 through an oxidation-olefination-reduc-
tion sequence.6 Because a method to remove a cyano
group on the benzocyclobutene ring had been estab-
lished,7 we hastened to try the asymmetric oxidation of
compound 7 and acetonization. Although the Sharpless
(8) While the product 9 afforded a corresponding ketone upon
treatment with PDC, the isomeric side product gave an aldehyde by
the same oxidation, which supported the structure determination of
the acetonides.
(9) Roush, W. R.; Brown, R. J.; DiMare, M. J. Org. Chem. 1983, 48,
5083-5093.
(10) The optical purity (95% ee) was estimated by the NMR spectra
of the corresponding MTPA ester, and the absolute configuration was
presumed from the empirical rule for the Sharpless asymmetric
epoxidation. The diastereomers originating from a chiral center on the
carbon bearing the cyano group were indistinguishable in the spectra.
(11) The product 2a obtained from these manipulations was trans-
formed into the final compound 5a, which showed no optical rotation.
(12) The [R]D value of the final compound 5a synthesized from 2a
thus obtained was +93.5 (c 0.4, MeOH).
(5) Kametani, T.; Kato, Y.; Honda, T.; Fukumoto, K. J. Am. Chem.
Soc. 1976, 98, 8185-8190.
(6) Nemoto, H.; Satoh, A.; Fukumoto, K. J. Chem. Soc., Perkin Trans.
1 1994, 943-946.
(7) Nemoto, H.; Nagai, M.; Abe, Y.; Moizumi, M.; Fukumoto, K. J.
Chem. Soc., Perkin Trans. 1 1987, 1727-1733.
(13) Jackson, D. Y. Synth. Commun. 1988, 18, 337-341.
J. Org. Chem, Vol. 70, No. 17, 2005 6899

Matsuya et al.
SCHEME 4a
corresponding aldehyde (2,3-O-isopropylideneglyceralde-
hyde),16 and recent reports have dealt with a particular
substrate containing a chelatable dithioacetal15b or furan15a
substructure adjacent to the carbonyl group, making the
prediction of a suitable condition for our substrates 2
difficult. Therefore, several conditions were examined on
nucleophilic addition of isopropenyl metal reagents to the
chiral ketone 2a, and a summary of the results is given
in Table 1. When the ketone 2a was exposed to 2-lithio-
propene in THF at -78 °C, the adduct 3a was obtained
in a good yield; but disappointing stereoselectivity was
observed with the predominant formation of undesired
syn adduct (entry 1). The corresponding zinc reagent gave
no adduct under the same condition (entry 2). On the
other hand, gratifyingly, it was found that the requisite
anti-3a was formed with a high diastereoselectivity by
utilizing 2-propenylmagnesium bromide as a reagent
(entry 3). A comparable result was obtained in less polar
and non-Lewis basic solvent (toluene), and the selectivity
was kept relatively high even at room temperature (entry
4-6), implying that the reaction course was controlled
by a tight transition state including, presumably, R-che-
lation of the magnesium metal rather than the â-chela-
tion or Felkin-Anh nonchelation model.17 The TBS
derivative 2b was also subjected to the same reaction
condition to afford anti-3b exclusively in a high yield
(entry 7). Because available information on such excep-
tionally high stereoselectivity of the Grignard addition
was quite limited from literature as mentioned above,18
we felt a great interest in the generality of the reaction.
Accordingly, the simple chiral ketones 15 and 16 were
prepared19 and subjected to the Grignard addition reac-
tion under the optimized condition. This investigation
revealed that high anti selectivity was realized in every
case as shown in Scheme 5,20 suggesting that these types
of chiral ketones were versatile substrates for chiral
syntheses through the 1,2-asymmetric induction process
with a wide generality.
a Reagents and conditions: (a) DIBAL, CH2Cl2; (b) PPh3, CBr4,
CH2Cl2; (c) n-BuLi (2 equiv), THF; (d) n-BuLi (1 equiv), THF, (R)-
2,2-dimethyl-1,3-dioxolane-4-carbaldehyde; (e) H2, Pd/C, THF; (f)
TPAP, NMO, MS4A, CH2Cl2.
formyl group by DIBAL reduction, and then alkynylation
via dibromoalkene 12a was performed. Lithiation of the
resulting alkyne 13a followed by exposure to (R)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde gave the alcohol
14a as a mixture of diastereomers (ratio not determined)
in 35% yield accompanied by a 61% yield of the starting
alkyne,14 which was recyclable without any loss (90%
yield based on the consumed starting material). Of
course, one-pot transformation of 12a to 14a by succes-
sive treatment with n-BuLi and the chiral aldehyde was
also possible with a comparable yield. Hydrogenation of
the triple bond and TPAP oxidation of the hydroxyl group
proceeded in satisfactory yields to provide 2a, which was
confirmed to be identical with that synthesized in Scheme
3 with regard to the spectral and physical data. In
addition, another derivative (2b) having an easily remov-
able TBS group was synthesized from 1b via the same
pathway. Thus, a highly concise approach to the com-
pounds 2 was established in 5 steps from 1, in contrast
to the required 14 steps in Scheme 3.
2. Diastereoselective Addition to Chiral Ketones
2. The next phase of the study was introduction of an
isopropenyl group to the chiral ketones 2, accompanied
by 1,2-asymmetric induction. Precedent studies on the
diastereoselective addition to analogous ketones, having
the adjacent chiral dimethyldioxolane moiety, have re-
vealed that the stereochemical course of the reaction is
highly dependent on the counter metal of carbon nucleo-
philes and reaction conditions (solvent, temperature,
additive, and so on).15 However, only a few studies have
been reported on this subject so far compared with the
3. Thermal Transformation of 3 to A-Nor Steroi-
dal Ketones 5. For the two substrates 3a and 3b, the
key thermal reaction involved in the synthetic strategy
was performed to achieve an efficient construction of the
target A-nor C,D-trans steroidal skeleton in a highly
stereoselective fashion (Scheme 6). The stereochemical
course of the reaction should be directed by four possible
transition states in the [4+2] cycloaddition step,1 and the
stereostructure of products 4a and 4b indicated that the
reaction proceeded via the transition state presented in
Scheme 1, because the others were much more congested
due to the bulkiness of the dimethyldioxolane moiety.
Compound 4a was subjected to a one-pot transformation
into ketone 5a by treatment with periodic acid, including
(16) Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447-
488 and references therein.
(17) Considerations of these reaction models are described in the
previous papers: see refs 15a-c.
(18) With regard to a different trend of the stereoselectivity between
the ketones utilized here and the corresponding aldehyde, higher Lewis
basicity of the ketone carbonyl groups compared to that of the aldehyde
may affect the stereochemical outcome.
(19) Preparative methods for compounds 15 and 16 are provided in
the Supporting Information.
(20) Although the relative configurations of the adducts 17 and 18
were deduced on the basis of the empirical rule (Landmann, B.;
Hoffmann, R. W. Chem. Ber. 1987, 120, 331-339), those of 3a and 3b
were determined by NOE experiments after conversion to 4 (ref 3).
(14) The corresponding zinc acetylide was prepared in situ to
decrease the basicity of the reagent, and subsequent reaction with the
aldehyde was examined, but ended in failure.
(15) (a) Tsubuki, M.; Tarumoto, N.; Honda, T. Heterocycles 2001,
54, 341-350. (b) Chikashita, H.; Nakamura, Y.; Uemura, H.; Itoh, K.
Chem. Lett. 1992, 439-442. (c) Chikashita, H.; Nikaya, T.; Uemura,
H.; Itoh, K. Bull. Chem. Soc. Jpn. 1989, 62, 2121-2123. (d) Hagen,
S.; Lwande, W.; Kilaas, L.; Anthonsen, T. Tetrahedron 1980, 36, 3101-
3105. (e) Meric, R.; Vigneron, J.-P. Bull. Soc. Chim. Fr. 1973, 327-
330.
6900 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of trans-4,5-Benzhydrindan-1-ones
TABLE 1. Diastereoselective Addition of Isopropenyl Metal Reagents to Ketones 2
entry
substrate
metal
solvent
temp (°C)
anti/syn
35/65
yield (%)
1
2
3
4
5
6
2a
2a
2a
2a
2a
2a
Li
THF
-78
-78
-78
-78
rt
70
0
90
87
91
87
ZnCl
MgBr
MgBr
MgBr
MgBr
THF
THF
95/5
95/5
92/8
85/15
toluene
THF
toluene
rt
7
2b
MgBr
THF
-78
100/0
93
SCHEME 5
1-ones 5a-c was accomplished with high efficiency and
high optical purity with use of o-quinodimethane chem-
istry.
Conclusion
In this study, we have developed a new synthetic route
to optically active trans-4,5-benzhydrindan-1-ones, which
are useful substrates for syntheses of A-nor steroidal
compounds. Through the described synthetic pathway,
the target tricyclic ketones 5 were synthesized in 9 steps
and 26-30% overall yield, starting from the benzocy-
clobutenes 1. The simplicity and conciseness of the
method described herein should provide a convenient
access to various biologically important steroids. Further
work on applying this methodology to the synthesis of
several bioactive compounds is actively in progress in our
laboratory.
acid-induced acetal cleavage and concurrent oxidative
degradation. However, an HPLC analysis21 of the result-
ing 5a indicated relatively low enantiomeric excess (88%
ee), which suggested that the cycloadduct 4a contained
a small amount of stereoisomer, presumably 4′. Because
we could not separate the isomer at this stage, compound
4a was transiently converted to triol 22, which could be
purified by column chromatography to remove the iso-
mer. The final ketone 5a resulting from 22 showed an
improved optical purity (93% ee), and the absolute
configuration was determined based on the sign of the
specific rotation.2c On the other hand, the TBS derivative
3b afforded 4b in a pure form, without any contamination
of the stereoisomers. This compound was directly oxidized
upon treatment with periodic acid to give the desilylated
ketone 5c in 52% yield (91% ee),22 accompanied by 5b
(17% yield). The structure and the optical purity of
product 5c were determined after conversion to the
known compound 5a (MeI, K2CO3, DMF, quantitative
yield). Thus, the synthesis of trans-4,5-benzhydrindan-
Experimental Section
4-(tert-Butyldimethylsilyloxy)benzocyclobutene-1-car-
bonitrile (1b). 4-hydroxybenzocyclobutene-1-carbonitrile was
prepared by demethylation of 1a5 according to the reported
method.23 To a solution of the hydroxybenzocyclobutene (1.10
g, 7.5 mmol) and triethylamine (1.26 mL, 9.1 mmol) in
anhydrous CH2Cl2 (25 mL) was added TBSOTf (1.9 mL, 8.3
mmol) dropwise at 0 °C, and the mixture was stirred at room
temperature for 1.5 h. The reaction mixture was diluted with
3% HCl aqueous solution and extracted with Et2O, and the
SCHEME 6a
a Reagents and conditions: (a) o-dichlorobenzene, reflux; (b) p-TsOH, MeOH; (c) HIO4, THF, H2O.
J. Org. Chem, Vol. 70, No. 17, 2005 6901

Matsuya et al.
organic layer was washed with saturated NaHCO3 and brine,
successively, and then dried over MgSO4. The solvent was
evaporated to leave a residue, which was chromatographed
on silica gel (CH2Cl2) to give silyl ether 1b (1.9 g, 97%) as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.06 (d, J ) 8.2 Hz,
1H), 6.77 (ddd, J ) 8.2, 2.2, 1.0 Hz, 1H), 6.63 (d, J ) 1.0 Hz,
1H), 4.15 (dd, J ) 5.7, 2.8 Hz, 1H), 3.59 (dd, J ) 14, 5.7 Hz,
1H), 3.46 (dd, J ) 14, 2.8 Hz, 1H), 0.98 (s, 9H), 0.19 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 157.1, 143.6, 131.1, 123.9, 121.0,
1H), 0.98 (s, 9H), 0.18 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
155.9, 143.9, 136.8, 123.0, 120.0, 115.3, 84.8, 70.1, 37.9, 31.0,
25.9, 18.4, -4.1; IR (neat) 2120 cm-1; MS (EI) m/z 258 (M+);
HRMS (EI) calcd for C16H22OSi 258.1440 (M+), found 258.1429.
(+)-4-(tert-Butyldimethylsilyloxy)-1-[3-(2,2-dimethyl-
1,3-dioxolan-4-yl)-3-hydroxy-1-propyn-1-yl]benzocyclo-
butene (14b). Method A: A solution of alkyne 13b (52 mg,
0.2 mmol) in THF (3 mL) was cooled to -78 °C and treated
with n-BuLi (1.6 M in hexane, 0.13 mL, 0.2 mmol) at the same
temperature for 20 min. Then, a solution of (R)-2,2-dimethyl-
1,3-dioxolane-4-carbaldehyde (130 mg, 1 mmol) in THF (1 mL)
was added to the mixture, and the resulting solution was
stirred at -78 °C for 1 h. The reaction was quenched by
addition of saturated NH4Cl, and the aqueous mixture was
extracted with CH2Cl2. After the solution was dried over
MgSO4, the solvent was evaporated to leave a residue, which
was chromatographed on silica gel (CH2Cl2-AcOEt, 9:1) to
afford alcohol 14b (39 mg, 50%) as a colorless oil. The starting
alkyne 13b (24 mg, 46%) was also recovered. Method B: A
solution of alkene 12b (170 mg, 0.4 mmol) in THF (3 mL) was
cooled to -78 °C, and n-BuLi (1.6 M in hexane, 0.53 mL, 0.85
mmol) was added to the solution. After 0.5 h, a solution of (R)-
2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (156 mg, 1.2 mmol)
in THF (2 mL) was added. The same workup as in Method A
120.1, 115.5, 35.8, 28.2, 26.0, 18.5, -4.1; IR (neat) 2238 cm-1
;
MS (EI) m/z 259 (M+); HRMS (EI) calcd for C15H21NOSi
259.1392 (M+), found 259.1437.
4-(tert-Butyldimethylsilyloxy)benzocyclobutene-1-car-
baldehyde (11b). To a solution of nitrile 1b (4.0 g, 15.4 mmol)
in anhydrous CH2Cl2 (45 mL) was added DIBAL (0.95 M in
hexane, 19.4 mL, 19.0 mmol) at -78 °C, and the mixture was
stirred at the same temperature for 0.5 h. After addition of
saturated NH4Cl solution, the aqueous mixture was vigorously
stirred at room temperature for 0.5 h. The precipitates formed
were 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 (CH2Cl2) to afford aldehyde 11b (3.3
1
g, 81%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 9.70
1
(d, J ) 3.6 Hz, 1H), 7.01 (d, J ) 7.9 Hz, 1H), 6.73 (dd, J ) 7.9,
1.1 Hz, 1H), 6.66 (s, 1H), 4.15-4.12 (m, 1H), 3.38-3.34 (m,
2H), 0.98 (s, 9H), 0.19 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
200.1, 156.5, 145.0, 133.0, 124.3, 120.3, 115.5, 53.1, 30.4, 26.0,
18.5, -4.1; IR (neat) 1721 cm-1; MS (EI) m/z 262 (M+); HRMS
(EI) calcd for C15H22O2Si 262.1389 (M+), found 262.1400.
gave 14b (83 mg, 53%) and 13b (34 mg, 32%). H NMR (300
MHz, CDCl3) δ 6.97 (d, J ) 8.0 Hz, 1H), 6.70 (d, J ) 8.0 Hz,
1H), 6.59 (s, 1H), 4.52-3.85 (m, 5H), 3.49 (dd, J ) 14, 5.2 Hz,
1H), 3.15 (d, J ) 14 Hz, 1H), 2.34 (br, 1H), 1.44 (s, 3H), 1.37
(s, 3H), 0.97 (s, 9H), 0.17 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 155.9, 143.9, 136.8, 136.7, 123.0, 120.0, 115.3, 110.5, 110.1,
87.3, 79.1, 79.0, 78.2, 66.4, 65.4, 64.8, 62.8, 38.0, 31.2, 31.1,
27.0, 26.6, 26.0, 25.6, 25.5, 18.4, -4.2; IR (neat) 3471, 2220
cm-1; MS (EI) m/z 388 (M+); HRMS (EI) calcd for C22H32O4Si
4-(tert-Butyldimethylsilyloxy)-1-(2,2-dibromoethenyl)-
benzocyclobutene (12b). To a solution of triphenylphosphine
(26.3 g, 97.5 mmol) in anhydrous CH2Cl2 (250 mL) was added
tetrabromomethane (16.2 g, 48.8 mmol), and the resulting
mixture was stirred at 0 °C for 0.5 h. A solution of aldehyde
11b (2.56 g, 9.8 mmol) in anhydrous CH2Cl2 (20 mL) was added
to the mixture, which was further stirred at room temperature.
After 0.5 h, the reaction mixture was diluted with saturated
NaHCO3 and filtered through a Celite pad. The organic layer
of the filtrate was separated and dried over MgSO4, and then
evaporated. The residue was subjected to column chromatog-
raphy (CH2Cl2-hexane, 1:1) to afford the alkene 12b (4.0 g,
388.2070 (M+), found 388.2075; [R]25 +15.3 (c 1.00, CHCl3).
D
(+)-4-(tert-Butyldimethylsilyloxy)-1-[3-(2,2-dimethyl-
1,3-dioxolan-4-yl)-3-oxoprop-1-yl]benzocyclobutene (2b).
A mixture of alkyne 14b (694 mg, 1.8 mmol) and 10% Pd/C
(80 mg) in THF (6 mL) was vigorously stirred under H2
atmosphere at room temperature for 20 h. The catalyst was
removed by filtration, and the filtrate was concentrated in
vacuo to give the saturated product (620 mg, 88%) as an almost
pure form. The product thus obtained (196 mg, 0.5 mmol) was
dissolved in anhydrous CH2Cl2 (10 mL), and molecular sieves
4A (200 mg), NMO (117 mg, 1.0 mmol), and TPAP (18 mg,
0.05 mmol) were added successively. The resulting mixture
was stirred at room temperature for 5 min, and then filtered
through a Celite pad. The residue obtained by concentration
of the filtrate was subjected to column chromatography (hex-
ane-AcOEt, 3:1) to afford the ketone 2b (166 mg, 83%) as a
1
98%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 6.95 (d,
J ) 8.0 Hz, 1H), 6.68 (d, J ) 8.0 Hz, 1H), 6.61 (d, J ) 9.1 Hz,
1H), 6.59 (s, 1H), 4.23-4.18 (m, 1H), 3.50 (dd, J ) 14, 5.5 Hz,
1H), 2.93 (d, J ) 14 Hz, 1H), 0.98 (s, 9H), 0.18 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 156.0, 144.0, 140.3, 137.9, 123.6,
119.9, 115.2, 89.5, 44.9, 36.2, 26.0, 18.5, -4.1; IR (neat) 1594
cm-1; MS (EI) m/z 415 (M+); HRMS (EI) calcd for C16H22Br2-
OSi 415.9807 (M+), found 415.9820.
1
colorless oil. H NMR (300 MHz, CDCl3) δ 6.90 (dd, J ) 8.0,
4-(tert-Butyldimethylsilyloxy)-1-ethynylbenzocyclo-
butene (13b). A solution of alkene 12b (143 mg, 0.34 mmol)
in THF (3 mL) was cooled to -78 °C, and n-BuLi (1.6 M in
hexane, 0.53 mL, 0.85 mmol) was added to the solution. After
continuous stirring at the same temperature for 0.5 h, the
reaction was quenched by addition of saturated NH4Cl, and
the aqueous mixture was extracted with CH2Cl2. The organic
layer was dried over MgSO4, and evaporated to leave a residue,
which was chromatographed on silica gel (CH2Cl2-hexane, 1:2)
3.1 Hz, 1H), 6.64 (d, J ) 8.0 Hz, 1H), 6.58 (s, 1H), 4.44-4.38
(m, 1H), 4.20-4.14 (m, 1H), 3.99-3.92 (m, 1H), 3.39-3.35 (m,
1H), 3.23 (dd, J ) 14, 5.2 Hz, 1H), 2.74 (t, J ) 7.4 Hz, 2H),
2.66 (d, J ) 14 Hz, 1H), 2.04-1.87 (m, 2H), 1.48 (s, 3H), 1.39
(s, 3H), 0.98 (s, 9H), 0.17 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 210.4, 155.3, 144.0, 140.8, 122.8, 118.9, 115.3, 110.9, 80.3,
66.6, 66.5, 41.7, 36.9, 36.8, 35.2, 27.8, 27.7, 26.2, 25.9, 25.2,
25.1, 18.3, -4.2; IR (neat) 1718 cm-1; MS (EI) m/z 390 (M+);
HRMS (EI) calcd for C22H34O4Si 390.2226 (M+), found 390.2182;
1
[R]25 +31.1 (c 1.00, CHCl3).
to afford alkyne 13b (76 mg, 85%) as a colorless oil. H NMR
D
(300 MHz, CDCl3) δ 7.00 (d, J ) 8.1 Hz, 1H), 6.71 (d, J ) 8.1
Hz, 1H), 6.59 (s, 1H), 4.10 (dd, J ) 5.0, 2.6 Hz, 1H), 3.51 (dd,
J ) 14, 5.0 Hz, 1H), 3.18 (d, J ) 14 Hz, 1H), 2.27-2.25 (m,
(+)-4-(tert-Butyldimethylsilyloxy)-1-[3-(2,2-dimethyl-
1,3-dioxolan-4-yl)-3-hydroxy-2-methyl-1-penten-5-yl]ben-
zocyclobutene (3b). To a solution of ketone 2b (146 mg, 0.4
mmol) in THF (10 mL) was added isopropenylmagnesium
bromide (0.8 M in THF, 1.5 mL, 1.2 mmol) at -78 °C, and the
reaction mixture was stirred at the same temperature for 1 h.
The reaction was quenched with saturated NH4Cl, and the
aqueous solution was extracted with Et2O and then dried over
MgSO4. Evaporation of the solvent gave a residue, which was
chromatographed on silica gel (hexane-AcOEt, 3:1) to afford
(21) The analytical condition for the determination of the optical
purity of 5a using HPLC has been described in ref 3.
(22) The optical purity of product 5c (91% ee) was somewhat lower
than expected. This may be attributed to a partial loss of the optical
purity of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde used during
the preparation or the reaction with the acetylide.
(23) Matsuya, Y.; Sasaki, K.; Nagaoka, M.; Kakuda, H.; Toyooka,
N.; Imanishi, N.; Ochiai, H.; Nemoto, H. J. Org. Chem. 2004, 69, 7989-
7993.
1
the alcohol anti-3b (149 mg, 93%) as a colorless oil. H NMR
(300 MHz, CDCl3) δ 6.89 (d, J ) 7.9 Hz, 1H), 6.63 (d, J ) 7.9
6902 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of trans-4,5-Benzhydrindan-1-ones
Hz, 1H), 6.57 (s, 1H), 5.10 (s, 1H), 5.02-5.00 (m, 1H), 4.31-
4.25 (m, 1H), 4.04-3.95 (m, 2H), 3.31-3.29 (m, 1H), 3.22 (dd,
J ) 14, 3.2 Hz, 1H), 2.61 (dd, J ) 14, 11 Hz, 1H), 1.95 (br,
1H), 1.77 (d, J ) 7.1 Hz, 3H), 1.73-1.47 (m, 4H), 1.43 (s, 3H),
1.38 (s, 3H), 0.97 (s, 9H), 0.17 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 155.2, 146.5, 144.3, 122.7, 118.9, 115.4, 112.7, 109.2,
79.0, 76.5, 65.1, 42.6, 35.6, 35.4, 32.6, 28.3, 26.6, 26.0, 25.7,
20.2, 18.5, -4.1; IR (neat) 3565 cm-1; MS (EI) m/z 432 (M+);
HRMS (EI) calcd for C25H40O4Si 432.2696 (M+), found 432.2687;
saturated NaHCO3, the aqueous mixture was extracted with
CH2Cl2 and then dried. The solvent was evaporated off, and
the residue was subjected to silica gel column chromatography
(CH2Cl2-AcOEt, 20:1) to afford 5b (5.2 mg, 17%) and 5c (11
mg, 52%) as colorless solids. 5b: mp 87-89 °C; 1H NMR (300
MHz, CDCl3) δ 6.96 (d, J ) 7.7 Hz, 1H), 6.68-6.65 (m, 2H),
2.96-2.87 (m, 3H), 2.68-2.29 (m, 1H), 2.45-2.27 (m, 2H),
1.98-1.73 (m, 3H), 0.98 (s, 9H), 0.71 (s, 3H), 0.19 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 220.3, 154.0, 137.8, 130.7, 126.0,
120.1, 117.5, 48.2, 46.2, 36.8, 29.1, 26.8, 26.0, 21.7, 18.5, 14.3,
-4.1; IR (KBr) 1738 cm-1; MS (EI) m/z 330 (M+); HRMS (EI)
[R]25 +6.6 (c 1.00, CHCl3).
D
(-)-7-(tert-Butyldimethylsilyloxy)-3-(2,2-dimethyl-1,3-
dioxolan-4-yl)-3-hydroxy-3a-methyl-2,3,3a,4,5,9b-hexahy-
dro-1H-cyclopenta[a]naphthalene (4b). A solution of 3b
(35 mg, 0.08 mmol) in o-dichlorobenzene (5 mL) was refluxed
for 5 h. Removal of the solvent left a residue, which was
chromatographed on silica gel (CH2Cl2-AcOEt, 10:1) to afford
calcd for C20H30O2Si 330.2015 (M+), found 330.1983; [R]25
D
+57.8 (c 0.55, CHCl3). 5c: mp 150-152 °C; 1H NMR (300 MHz,
CDCl3) δ 6.99-6.96 (m, 1H), 6.69-6.59 (m, 2H), 5.02 (br, 1H),
2.95-2.86 (m, 3H), 2.72-2.61 (m, 1H), 2.46-2.27 (m, 2H),
1.98-1.73 (m, 3H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
207.5, 154.1, 138.0, 130.0, 126.2, 115.2, 112.8, 48.0, 45.9, 36.5,
28.7, 26.4, 21.4, 13.9; IR (KBr) 3400, 1718 cm-1; MS (EI) m/z
216 (M+); HRMS (EI) calcd for C14H16O2 216.1150 (M+), found
1
cycloadduct 4b (31 mg, 88%) as a colorless oil. H NMR (300
MHz, CDCl3) δ 6.86 (d, J ) 8.0 Hz, 1H), 6.61-6.58 (m, 2H),
4.36 (t, J ) 7.2 Hz, 1H), 3.97-3.93 (m, 2H), 3.28-3.21 (m, 1H),
2.88-2.82 (m, 2H), 2.26-2.17 (m, 1H), 2.00-1.90 (m, 1H),
1.84-1.70 (m, 3H), 1.63-1.50 (m, 2H), 1.45 (s, 3H), 1.37 (s,
3H), 0.98 (s, 9H), 0.67 (s, 3H), 0.18 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 153.2, 137.3, 133.3, 126.9, 119.6, 117.1, 109.2, 81.5,
78.4, 65.6, 48.0, 45.5, 33.3, 29.0, 27.3, 26.8, 26.0, 25.5, 24.3,
18.5, 15.1, -4.1; IR (neat) 3565 cm-1; MS (EI) m/z 432 (M+);
HRMS (EI) calcd for C25H40O4Si 432.2696 (M+), found 432.2701;
216.1140; [R]25 +73.1 (c 0.53, CHCl3).
D
Acknowledgment. This work was supported par-
tially by a Grant-in-Aid (No. 15390004) for Scientific
Research by the Ministry of Education, Culture, Sports,
Science, and Technology of the Japanese Government.
[R]25 -4.7 (c 0.81, CHCl3).
D
(+)-7-(tert-Butyldimethylsilyloxy)-3a-methyl-1,2,3a,4,5,
9b-hexahydro-3H-cyclopenta[a]naphthalen-3-one (5b) and
(+)-7-Hydroxy-3a-methyl-1,2,3a,4,5,9b-hexahydro-3H-cy-
clopenta[a]naphthalen-3-one (5c). To a solution of 4b (40
mg, 0.09 mmol) in THF (3 mL) and H2O (3 mL) was added
periodic acid hydrate (105 mg, 0.46 mmol), and the mixture
was stirred at room temperature for 22 h. After dilution with
Supporting Information Available: Synthetic procedure
and characterization data for the compounds 6-9, 11a-14a,
and 15-18, and NMR spectra of the compounds 2a, 11a-14a,
1b-5b, 5c, and 11b-14b. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO051060W
J. Org. Chem, Vol. 70, No. 17, 2005 6903