A novel approach to bicyclic fused cyclopentenone derivatives

Article abstract of DOI:10.1016/S0040-4039(02)02579-0

A new four-step reaction sequence leading to bicyclic fused cyclopentenone derivatives starting from cyclic ketones has been developed.

Full text of DOI:10.1016/S0040-4039(02)02579-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 587–589
A novel approach to bicyclic fused cyclopentenone derivatives
Guisheng Deng, Xue Tian and Jianbo Wang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology,
College of Chemistry, Peking University, Beijing 100871, PR China
Received 20 August 2002; revised 31 October 2002; accepted 8 November 2002
Abstract—A new four-step reaction sequence leading to bicyclic fused cyclopentenone derivatives starting from cyclic ketones has
been developed. © 2002 Elsevier Science Ltd. All rights reserved.
Bicyclic fused cyclopentenone derivatives are important
structural units in natural product synthesis. Therefore,
these types of bicyclic compounds have attracted atten-
tion from synthetic organic chemists over decades and
various approaches have been developed.1 For example,
the Pauson–Khand reaction recently emerged as a pow-
erful tool to construct bicyclic cyclopentenone struc-
tures.2 In connection with research in the application of
a-diazo carbonyl compounds in organic synthesis,3 we
have developed a new method for synthesizing bicyclic
fused cyclopentenone derivatives based on an
intramolecular CꢀH bond insertion by Rh(II) carbene
(Scheme 1).
Next, we proceeded to convert the alcohols 3a–g to
a,b-unsaturated carbonyl compounds 4a–g. However,
because of the steric hindrance, the tertiary hydroxyl
Scheme 1.
Thus, the nucleophilic addition to cyclic ketones 1a–d
by Ti(IV) enolates 2a–b derived from an a-diazo-b-keto
ester or a ketone is expected to give alcohols 3a–g
(Scheme 2). Although the similar aldol condensation of
an a-diazo-b-ketoester with aldehydes has been devel-
oped by Calter et al.,4 the corresponding reaction with
ketones has not been reported.5 When Calter’s reaction
conditions (TiCl4/Et3N, −78°C/CH2Cl2) were applied to
the condensation of ethyl 2-diazoacetoacetate with
cyclohexanone 1b, the reaction was found to proceed
very slowly. Obviously, the carbonyl group of a ketone
is less reactive than that of aldehydes. To improve the
reactivity, the cyclohexanone was activated with 1
equiv. of Ti(OiPr)4 before adding to the Ti(IV) enolate.
Moreover, the reaction temperature was raised to
−23°C with dry ice/CCl4. Under these conditions, the
nucleophilic addition occurred at an acceptable rate to
give the expected alcohols in reasonable yields (Table
1).6
Keywords: Ti(IV) enolate; nucleophilic addition; Rh(II) carbene;
intramolecular C–H insertion.
* Corresponding author.
Scheme 2.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02579-0

588
G. Deng et al. / Tetrahedron Letters 44 (2003) 587–589
Table 1. Nucleophilic condensation of 1a–d with 2a–b and dehydration of 3a–g
Entry
1a–b 2a–b Reaction time (h)
Yield (%) of 3a–ga
3a–g Reaction time (h)
Ratio 4:5b
Yield (%) (4+5)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1a
1b
1c
2a
2a
2a
2a
2b
2b
2b
9
84
85
64
58
40
56
58
3a
3b
3c
3d
3e
3f
17
23
23
16
15
17
17
3.5:1
100:0
3:1
2:1
7:1
85
84
74
66
56
62
67
9.5
5.3
8.5
9
8
7
100:0
6:1
3g
a Yields after silica gel column chromatography.
b Ratio was determined by 1H NMR (200 MHz) of the crude product.
group was found to be inert to many reagents. After
examining the dehydration of the alcohol under various
conditions, we finally found that (CF3CO)2O/Et3N can
effectively dehydrate the alcohols at room temperature
in CH2Cl2. An inseparable mixture of 4a–g and 5a–g
was obtained in moderate to good yields. Similar results
were obtained with other substrates (Table 1).7 The
ratios of 4a–g to 5a–g vary according to the ring size of
the cyclic alkane moiety, but the compounds 4a–g
dominate in all cases. For the alcohols 3b and 3f, 4b
and 4f were the only products (entries 2 and 6, Table 1).
Since the mixtures of 4a–g and 5a–g were not separable
by silica gel column chromatography, they were sub-
jected to the Rh(II)-mediated diazo decomposition
without further purification. The diazo decomposition
with Rh2(OAc)4 gave a complex mixture. As it is
known that the ligands of the Rh(II) catalyst can
dramatically affect the diazo decomposition reaction,8
we decided to examine other Rh(II) catalysts. To our
delight, the diazo decomposition of a mixture of 4a and
Scheme 4.
ture of this product was shown to be cis-1-carboethoxy
bicyclo[4,3,0]-non-3-en-2-one 6a (Scheme 3).9 For other
diazo substrates, similar results were obtained (Table
2).10
It is interesting to note that the Rh2(NHCOCH3)4-cata-
lyzed reaction of the mixtures of 4a,c,d,g and 5a,c,d,g
gave 6a,c,d,g as the main isolated products. Two possi-
ble reaction pathways are conceivable for the transfor-
mation of 5a,c,d,g to 6a,c,d,g (Scheme 4). In pathway a,
there is an equilibrium between 4a and 5a. Diazo
compound 4a reacts faster under the catalytic condi-
tions to give 6a, thus driving the equilibrium to the
right. In pathway b, diazo compound 5a reacts with
Rh2(NHCOCH3)4 to give 7, which isomerizes to gener-
ate 6a.
5a with Rh2(NHCOCH3)4 cleanly gave
a major
product, which was separated in 72% yield. The struc-
In summary, we have developed a novel approach to
the two-ring fused cyclopentenone derivatives based on
Rh2(NHCOCH3)4-catalyzed diazo decomposition. This
novel reaction sequence has the advantages of high
efficiency, readily available starting materials and mild
reaction conditions. This approach should also be
applicable to the synthesis of other cyclopentenone
derivatives.
Scheme 3.
Table 2. Rh2(NHCOCH3)4-catalyzed intramolecular C–H
insertion
Entry
4a–g and
5a–ga
Reaction
time (h)
Products
Yield (%)b
1
2
3
4
5
a
b
c
d
g
2
2
3
2
5
6a
6b
6c
6d
6g
72
76
62
72
60
Acknowledgements
The project is generously supported by NSFC (Grant
No. 29972002, 20172002), the Trans-Century Training
Programme Foundation for the Talents by the Ministry
of Education.
a For Entry 5, 5 mol% of Rh2(NHCOCH3)4 was used; in all the other
cases, 1 mol% catalyst was used.
b Yields after silica gel column chromatography.

G. Deng et al. / Tetrahedron Letters 44 (2003) 587–589
589
References
NaHCO3 (2×20 mL), and then dried over Na2SO4. The
product was purified by flash chromatography to yield 3b
as a yellow oil (863 mg, 85%). IR (CCl4) 3514, 2135,
1. (a) Corey, E. J.; Ghosh, A. K. Tetrahedron Lett. 1987, 28,
175–178; (b) Polo, E.; Bellabarba, R. M.; Prini, G.;
Traverso, O.; Green, M. L. H. J. Organomet. Chem.
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A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 2000, 41,
6859–6863.
1
1721, 1638 cm−1; H NMR (200 MHz, CDCl3) l 1.34 (t,
J=7.2 Hz, 3H), 1.44–1.53 (m, 6H), 1.60–1.70 (m, 4H),
3.05 (s, 2H), 3.62 (s, 1H), 4.31 (q, J=7.2 Hz, 2H); 13C (50
MHz, CDCl3) l 14.1, 21.8, 25.5, 37.6, 49.0, 61.5, 71.3,
161.4, 193.0; MS (FAB) m/z 261 [(M+Li)+, 25], 241 (63),
233 (13), 187 (19), 143 (100), 121 (42), 97 (29).
7. General procedure for the dehydration of the alcohols
3a–g. Under N2, 3b (254 mg, 1 mmol) was dissolved in
anhydrous CH2Cl2 (10 mL) and the solution was cooled
to −78°C. While stirring, (CF3CO)2O (420 mg, 2 mmol)
and Et3N (202 mg, 2 mmol) were added and the reaction
temperature was allowed to rise to rt within 2 h. Another
5 mL Et3N was added and the reaction mixture was
stirred at rt for 23 h. Volatile fractions were removed by
rotovap to leave a crude residue, which was purified by
silica gel column chromatography to give 4b (198 mg,
2. For recent examples of bicyclic fused cyclopentenone
derivative syntheses based on the Pauson–Khand reac-
tion, see: (a) Sugihara, T.; Yamaguchi, M. J. Am. Chem.
Soc. 1998, 120, 10782–10783; (b) Perez-Serrano, L.;
Casarrubios, L.; Dominguez, G.; Perez-Castells, J. Org.
Lett. 1999, 1, 1187–1188; (c) Adrio, J.; Carretero, J. C. J.
Am. Chem. Soc. 1999, 121, 7411–7412; (d) Evans, P. A.;
Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609–4610;
(e) Brummond, K. M.; Kerekes, A. D.; Wan, H. J. Org.
Chem. 2002, 67, 5156–5163; (f) Shibata, T.; Toshida, T.;
Takagi, K. Org. Lett. 2002, 4, 1619–1621; (b) Sturla, S.
J.; Buchwald, S. L. J. Org. Chem. 2002, 67, 3398–3403.
3. For comprehensive reviews on a-diazo carbonyl com-
pounds, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with
Diazo Compounds; Wiley-Interscience: New York, 1998;
(b) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 44, 1091.
4. (a) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetra-
hedron Lett. 1997, 38, 3837–3840; (b) Calter, M. A.;
Sugathapala, P. M. Tetrahedron Lett. 1998, 39, 8813–
8816; (c) Calter, M. A.; Zhu, C. J. Org. Chem. 1999, 64,
1415–1419.
84%). IR (CCl4) 2134, 1717, 1645, 1444, 1362 cm−1 1H
;
NMR (200 MHz, CDCl3) l 1.33 (t, J=7.2 Hz, 3H),
1.62–1.72 (m, 6H), 2.23–2.39 (m, 2H), 2.81–2.87 (m, 2H),
4.29 (q, J=7.2 Hz, 2H), 6.81 (s, 1H); 13C NMR (50
MHz, CDCl3) l 14.3, 26.2, 27.9, 28.8, 30.7, 38.4, 61.2,
117.8, 161.5, 163.9, 182.6; MS (FAB) m/z 237 [(M+H)+,
22], 163 (9), 135 (10), 123 (19), 95 (41), 69 (64), 43 (100).
8. Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.;
Tran, A. J. Am. Chem. Soc. 1993, 115, 8669–8680.
9. The cis configuration of the product was assigned by
1
comparison with the H NMR data of the trans isomer
reported in Ref. 1c.
5. For a recent report on the reaction of Ti(IV) enolates
derived from a-diazo-b-ketoesters with a,b-unsaturated
carbonyl compounds, see: Deng, G.; Tian, X.; Qu, Z.;
Wang, J. Angew. Chem., Int. Ed. Engl. 2002, 41, 2773–
2776.
10. Typical procedure for the Rh2(NHCOCH3)4-catalyzed
reaction of diazo compounds 4a–g and 5a–g. To a solu-
tion of 4b (118 mg, 0.5 mmol) in anhydrous CH2Cl2 (10
mL) was added Rh2(NHCOCH3)4 (0.5 mg, 0.025 mmol).
The solution was stirred under N2 for 48 h. The solvent
was removed under reduced pressure to give a crude
residue, which was purified by column chromatography
to yield 6b (79 mg, 76%) as an oil. IR (CCl4) 1719, 1636,
1552, 1253 cm−1; 1H NMR (200 MHz, CDCl3) l 1.18 (dq,
J=13, 3.2 Hz, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.40 (tq,
J=13, 3.8 Hz, 1H), 1.54 (tq, J=13, 3.2 Hz, 1H), 1.88 (d,
J=13 Hz, 1H), 2.02–2.07 (m, 1H), 2.25–2.29 (m, 1H),
2.33 (dt, J=13, 5 Hz, 1H), 2.86 (d, J=13.9 Hz, 1H), 3.02
(s, 1H), 3.05 (d, J=3.8 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H),
5.82 (s, 1H); 13C NMR (50 MHz, CDCl3) l 14.1, 25.0,
26.5, 30.8, 33.9, 45.8, 59.3, 61.4, 124.9, 169.2, 184.1,
201.3; MS (EI) m/z 208 (M+, 28), 162 (32), 134 (100), 107
(15), 106 (20), 79 (22), 53 (8), 39 (22).
6. General procedure for the condensation of cyclic ketones
with a-diazo-b-ketoesters or ketones. To a solution of
ethyl 2-diazoacetoacetate (624 mg, 4 mmol) in anhydrous
CH2Cl2 (40 mL) at −23°C with dry ice/CCl4 under N2
was added dropwise TiCl4 (836 mg, 4.4 mmol) and Et3N
(444 mg, 4.4 mmol). After the resulting red-dark solution
was stirred at −23°C for 1 h, a solution of cyclohexanone
(392 mg, 4 mmol) and Ti(OiPr)4 (1136 mg, 4 mmol) in
anhydrous CH2Cl2 (4 mL) was added dropwise. The
reaction mixture was stirred at −23°C for 9.5 h and was
then quenched with saturated aqueous NH4Cl (10 mL).
The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (2×20 mL). The combined
organic layers were washed with saturated aqueous