A novel and facile synthesis of functionalized [4.4.3] and [4.4.4]propellano-bislactones using acetates of the Baylis-Hillman adducts.

Article abstract of DOI:10.1021/ol016469w

[reaction--see text] A simple and convenient synthesis of 11,16-di[(E)-arylidene]-13,14-dioxatetracyclo-[7.4.4.0.(1,9)0(2,7)]heptadeca-2,4,6-triene-12,15-diones and 12,17-di[(E)-benzylidene]-14,15-dioxatetracyclo[8.4.4.0.(1,10)0(2,7)]octadeca-2,4,6-triene

Full text of DOI:10.1021/ol016469w

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3619-3622
A Novel and Facile Synthesis of
Functionalized [4.4.3] and
[4.4.4]Propellano-bislactones Using
Acetates of the Baylis−Hillman Adducts
Deevi Basavaiah* and Tummanapalli Satyanarayana
School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India
dbsc@uohyd.ernet.in
Received July 20, 2001
ABSTRACT
A simple and convenient synthesis of 11,16-di[(E)-arylidene]-13,14-dioxatetracyclo-[7.4.4.0.1,902,7]heptadeca-2,4,6-triene-12,15-diones and 12,-
17-di[(E)-benzylidene]-14,15-dioxatetracyclo[8.4.4.0.1,1002,7]octadeca-2,4,6-triene-13,16-dione, i.e., 2,10-dioxa[4.4.3]propellane-3,9-diones and 2,-
10-dioxa[4.4.4]propellane-3,9-dione, using acetates of the Baylis−Hillman adducts has been described.
Carbocyclic and heterocyclic propellanes occupy a special
place in synthetic organic chemistry because of their
aesthetically appealing structural architecture.1 The polycyclic
polylactone framework is an important structural feature
present in various biologically active and natural products.2
The beautiful structural architecture of propellanes and
important biological properties of polylactones have attracted
our attention, and we herein report a simple and convenient
methodology for synthesis of functionalized propellano-
bislactones3 using acetates of the Baylis-Hillman adducts.
In recent years the Baylis-Hillman carbon-carbon bond
forming reaction has attracted the attention of organic
chemists as this reaction provides densely functionalized
molecules that have been used in a variety of interesting
organic transformations.4-6 In continuation of our interest
(4) (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653. (b)
Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R. Tetrahedron 1996, 52,
8001. (c) Ciganek, E. Organic Reactions; Paquette, L. A. Ed.; Wiley: New
York, 1997; Vol 51, p 201.
(5) (a) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729. (b) Aggarwal, V.
K.; Merue, A. Tarver, G. J.; McCague, R. J. Org. Chem. 1998, 63, 7183.
(c) Kim, H. S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J.; Kim, J.
N. Tetrahedron Lett. 2000, 41, 2613. (d) Barrett, A. G. M.; Cook, A. S.;
Kamimura, A. Chem. Commun. 1998, 2533. (e) Lee, W.-D.; Yang, K.-S.;
Chen, K. Chem. Commun. 2001, 1612. (f) Chamakh, A.; M’hirsi, M.;
Villieras, J.; Lebreton, J.; Amri, H. Synthesis 2000, 295. (g) Bosanac, T.;
Wilcox, C. S. Chem. Commun. 2001, 1618. (h) Shi, M.; Li, C.-Q.; Jiang,
J.-K. Chem. Commun. 2001, 833. (i) Ramachandran, P. V.; Venkat Ram
Reddy, M.; Rudd, M. T. Chem. Commun. 2001, 757. (j) Ra¨cker, R.; Do¨ring,
K.; Reiser, O. J. Org. Chem. 2000, 65, 6932. (k) Trost, B. M.; Tsui, H.-C.;
Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534. (l) Iwabuchi, Y.; Nakatani,
M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
(6) (a) Basavaiah, D.; Kumaragurubaran, N.; Sharada, D. S. Tetrahedron
Lett. 2001, 42, 85. (b) Basavaiah, D.; Kumaragurubaran, N. Tetrahedron
Lett. 2001, 42, 477. (c) Basavaiah, D.; Mallikarjuna Reddy, R. Tetrahedron
Lett. 2001, 42, 3025. (d) Basavaiah, D.; Sreenivasulu, B.; Srivardhana Rao,
J. Tetrahedron Lett. 2001, 42, 1147. (e) Basavaiah, D.; Sarma, P. K. S. J.
Chem. Soc., Chem. Commun. 1992, 955. (f) Basavaiah, D.; Gowriswari,
V. V. L.; Sarma, P. K. S.; Dharmarao, P. Tetrahedron Lett. 1990, 31, 1621.
(g) Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.; Sarma, P.
K. S.; Kumaragurubaran, N. J. Org. Chem. 1999, 64, 1197.
(1) (a) Zalkow, L. H.; Harris, III, R. N.; Derveer, D.V. J. Chem. Soc.,
Chem. Commun. 1978, 420. (b) Jamrozik, J.; Z˙ eslawski, W. Monatsh.
Chem. 1992, 123, 129. (c) Ginsburg, D. Acc. Chem. Res. 1969, 2, 121.
(d) Dave, P. R.; Forohar, F.; Axenrod, T.; Qi, L.; Watnick, C.; Yazdekhasti,
H. Tetrahedron Lett. 1994, 35, 8965. (e) Aped, P.; Fuchs, B.; Goldberg,
I.; Senderowitz, H.; Tartakovsky, E.; Weinman, S. J. Am. Chem. Soc.
1992, 114, 5585. (f) Rajamannar, T.; Balasubramanian, K. K. J. Chem.
Soc., Chem. Commun. 1994, 25. (g) Dave, P. R.; Forohar, F.; Axenrod, T.;
Das, K. K.; Qi, L.; Watnick, C.; Yazdekhasti, H. J. Org. Chem. 1996, 61,
8897.
(2) (a) Corey, E. J.; Kang, M.-C. J. Am. Chem. Soc. 1984, 106, 5384.
(b) Chen, M.-J.; Narkunan, K.; Liu, R.-S. J. Org. Chem. 1999, 64, 8311.
(c) Danishefsky, S.; Schuda, P. F.; Kitahara, T.; Etheredge, E. J. J. Am.
Chem. Soc. 1977, 99, 6066. (d) Yoshida, S.-I.; Ogiku, T.; Ohmizu, H.;
Iwasaki, T. J. Org. Chem. 1997, 62, 1310. (e) Cossy, J.; Gille, B.; Bellosta,
V. Tetrahedron Lett. 1998, 39, 4459.
(3) For propellano-lactones, see: (a) Ashkenazi, P.; Kapon, M.; Piantini,
U.; von Philipsborn, W.; Ginsburg, D. HelV. Chem. Acta. 1985, 68, 614.
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10.1021/ol016469w CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/19/2001

Scheme 1
in the development of Baylis-Hillman chemistry as a source
Accordingly, we have first selected methyl 3-acetoxy-3-
phenylpropanoate (1a) as an alkylating agent for bisalkylation
at the 2-position of 1-indanone. The best results were
achieved when the bisalkylation of 1-indanone (2) (2 mM)
was carried out with methyl 3-acetoxy-2-methylene-3-
phenylpropanoate (1a) (5 mM) in the presence of NaH (10
mM) (excess) in benzene as solvent at reflux, thus providing
the desired biscinnamic ester (3a) in 75% yield with high
(E)-stereoselectivity after column chromatography (silica gel,
15% EtOAc in hexanes).7 This compound is contaminated
with (Z)-isomer (∼12%) and other unidentified impurities
for useful organic transformation methodologies,6 we have
undertaken a research program on the application of Baylis-
Hillman adducts for the synthesis of functionalized propel-
lanes. Thus, we have envisaged that the bisalkylation at
2-position of 1-indanone with methyl 3-acetoxy-3-aryl-2-
methylenepropanoates (acetates of the Baylis-Hillman ad-
ducts) followed by hydrolysis would lead to the formation
of 2,2-bis[(2E)-2-carboxy-3-arylprop-2-en-1-yl]indan-1-ones.
Subsequent lactonization under appropriate conditions might
provide the desired propellano-bislactones (Scheme 1).
Table 1. Synthesis of Propellano-bislactones (1a f 3b f 4c f 5) and (1aa f 7ab f 8ac f 9a)
allyl
acetate
Ar
2 (n ) 1)/6 (n ) 2) productd 3, 7a yielde (%) productf 4, 8a yieldg (%) producth 5, 9a yieldi (%)
1a
1b
1c
1d
1e
1f
phenyl
2
2
2
2
2
2
2
6
3a
3b
3c
3d
3e
3f
75
74
70
77
74
66
81
59
4a
4b
4c
4d
4e
4f
71
70
75
72
70
73
72
81l
5a j
5bj
5cj
5d j,k
5ej
5f
92
91
84
89
86
90
85
68
4-methylphenyl
4-ethylphenyl
4-isopropylphenyl
2-chlorophenyl
4-chlorophenyl
4-methoxyphenyl
phenyl
1g
1a
3g
7a
4g
8a
5gj
9a k
a All the reactions were carried out on 2 mM scale of 1-indanone (2) [or 1-tetralone (6)] with 5 mM of the allyl acetate in the presence of excess NaH
(10 mM) in benzene at reflux for 30 h in N2 atm. b Hydrolysis was carried out on 1 mM scale of biscinnamic ester (3a-g, 7a) with KOH/MeOH (1 g in
4 mL) at room temperature for 3 h. c Bislactonization was carried out on 0.5 mM scale of biscinnamic acid (4a-g, 8a) with TFAA (1 mM) in CH2Cl2 (5
1
mL) at room temperature for 1.5 h in N2 atm. d All of the biscinnamic esters were obtained as colorless viscous liquids. H (200 MHz) and 13C (50 MHz)
NMR spectral data of compounds 3a-g indicate the presence of Z-isomer (ca. 5-15%) (in the case of 7a there is ∼18% Z-isomer) and also some unidentified
impurities (ca. 5-7%). e Yields of the biscinnamates (with impurities as mentioned in the above footnote) after column chromatography (silica gel, 15%
1
ethyl acetate in hexanes). f The compounds 4a-g were obtained as colorless solids with 100% (E)-stereochemistry and gave satisfactory IR and H (200
MHz) and 13C (50 MHz) NMR spectral data. The compound 8a was obtained as mixture of (E)- and (Z)-isomers in the ratio of ca. 85:15 and also contains
some unidentified impurities (∼ 5%). g Yields of the pure biscinnamic acids after crystallization from mixtures of EtOAc and hexanes. h All of the bislactones
were obtained as colorless crystalline solids and gave satisfactory IR and 1H (200 MHz) and 13C (50 MHz) NMR spectral data and elemental analyses.
i Yields of the pure bislactones after crystallization from mixtures of EtOAc and hexanes. j Compounds 5a-e and 5g were also characterized by mass
spectral data. k Structures of the compounds 5d and 9a were further confirmed by single-crystal X-ray data (Figures 1 and 2). l Yield of the biscinnamic acid
(8a) (E- & Z-isomers and with impurities as mentioned in the above footnote f).
3620
Org. Lett., Vol. 3, No. 23, 2001

of the Baylis-Hillman adducts (1a-g) into various propel-
lano-bislactones (5a-g, 9a) (Scheme 1, Table 1).
To ensure the formation of propellano-bislactones we
obtained single crystals in the case of 5d and 9a and
established the structures by X-ray crystallography data
(Figures 1 and 2).9
Figure 1. ORTEP diagram of compound 5d.
(∼5%). However, subsequent hydrolysis of this biscinnamic
ester (3a) as such, with KOH/MeOH followed by crystal-
lization from a mixture of EtOAc and hexanes (1:2),
furnished the desired biscinnamic acid (4a) with exclusive
(E)-stereochemistry in 71% yield.7 Bislactonization of this
biscinnamic acid (4a) was accomplished via treatment with
triflouroacetic anhydride (TFAA) in CH2Cl2 at room tem-
perature for 1.5 h to provide the desired 11,16-di[(E)-
benzylidene]-13,14-dioxatetracyclo[7.4.4.0.1,902,7]heptadeca-
2,4,6-triene-12,15-dione (5a) in 92% yield as a crystalline
solid.7,8 This result is indeed very encouraging. We then
successfully transformed a representative class of acetates
Figure 2. ORTEP diagram of compound 9a.
In conclusion, we have developed a simple and convenient
methodology for the preparation of functionalized dioxa-
(8) Spectral data for the compound 5a: mp ) 200-201 °C; IR (KBr)
1
1740, 1623 cm-1; H NMR (200 MHz) (CDCl3) δ 2.75 (dd, 2H, J ) 1.8
Hz, and 15.8 Hz),10 2.95 (d, J ) 1.8 Hz) & 3.02 (s) [4H],10 7.15-7.49 (m,
13H), 7.69-7.80 (m, 1H), 7.89 (s, 2H); 13C NMR (50 MHz) (CDCl3) δ
33.22, 42.55, 43.14, 111.88, 122.75, 124.28, 125.50, 128.25, 128.76, 129.54,
129.83, 131.02, 134.22, 139.29, 139.64, 143.86, 164.07; MS (m/z) 434 (M+).
Anal. Calcd for C29H22O4: C, 80.17; H, 5.10. Found: C, 80.11; H, 5.14.
(9) Detailed X-ray crystallographic data for the compound 5d and 9a
are available from the Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge, CB2 1EZ, U.K. (For 5d, CCDC no. 151753, and for 9a,
CCDC no. 155409). Crystal data for C35H34O4 (5d): M ) 518.62, colorless
crystal, crystal dimensions 0.7 × 0.6 × 0.6 mm3, monoclinic, space group
P21/n (No. 14), a ) 16.377(2) Å, b ) 10.404(3) Å, c ) 16.595(2) Å, â )
94.106° (11), V ) 2820.4(9) Å3, Z ) 4, Fcalcd ) 1.221 g cm-3, µ ) 0.079
mm-1, F(000) ) 1104, index ranges 0 e h e 19, 0 e k e 12, -19 e l e
19. θ range, 1.69-24.98°; 356 variables and 0 restraints were refined for
2048 independent reflections with I g 2σ(I) to R ) 0.0581, wR2 ) 0.1345,
GOF ) 1.044. Crystal data for C30H24O4 (9a): M ) 448.49, colorless
crystal, crystal dimensions 0.96 × 0.36 × 0.28 mm3, monoclinic, space
group P21/c (No. 14), a ) 8.9137 (10) Å, b ) 11.806 (4) Å, c ) 21.405(3)
Å, â ) 93.556° (10), V ) 2248.3 (8) Å3, Fcalcd ) 1.325 g cm-3, µ ) 0.087
mm-1, F(000) ) 944, index ranges from 0 e h e 10, 0 e k e 14, -25 e
l e 25. θ range 1.91-24.97°; 308 variables and 0 restraints were refined
(7) Typical Experimental Procedure (3a, 4a, 5a). (a) 2,2-Bis[(2E)-2-
methoxycarbonyl-3-phenylprop-2-en-1-yl]indan-1-one (3a). To oil-free NaH
(10 mM, 0.24 g) in dry benzene (15 mL) were added 1-indanone (2 mM,
0.264 g) and methyl 3-acetoxy-3-phenyl-2-methylenepropanoate (5 mM,
1.17 g) at room temperature, and the mixture was heated at 80 °C for 30 h
under N2 atmosphere with stirring. Then reaction mixture was allowed to
come to room temperature and cooled to 0 °C. Excess NaH was destroyed
by very slow and careful addition of acetic acid (1 mL). The reaction mixture
was diluted with water (15 mL) and extracted with ether (3 × 20 mL). The
combined organic layer was dried over anhydrous Na2SO4. Solvent was
evaporated, and the crude product thus obtained was purified by column
chromatography (15% ethyl acetate in hexanes) to provide 0.72 g (75%) of
3a as viscous liquid. This compound is contaminated with (Z)-isomer
(∼12%) and other unidentified impurities (∼5%). However, this was used
as such for hydrolysis as described in the following. (b) 2,2-Bis[(2E)-2-
carboxy-3-phenylprop-2-en-1-yl]indan-1-one (4a). To a stirred solution of
2,2-bis[(2E)-2-methoxycarbonyl-3-phenylprop-2-en-1-yl]indan-1-one (3a
obtained as above) (1 mM, 0.48 g) in MeOH (2 mL) was added a solution
of KOH (85% KOH pellets, 1 g) in MeOH (4 mL). After the mixture stirred
for 3 h at room temperature, MeOH was removed. Then the reaction mixture
was diluted with water (15 mL) and washed with ether (2 × 20 mL) to
remove any organic impurities. The aqueous layer was acidified with 2 N
HCl solution and extracted with ethyl acetate (3 × 20 mL). The combined
organic layer was dried over anhydrous Na2SO4 and concentrated. The crude
product thus obtained was purified by crystallization [ethyl acetate/hexanes
(1:2)] to provide biscinnamic acid (4a) as a crystalline solid (0.32 g, 71%)
with exclusive (E)-stereochemistry. (c) 11,16-Di[(E)-benzylidene]-13,14-
dioxatetracyclo[7.4.4.01,9.02,7]heptadeca-2,4,6-triene-12,15-dione (5a). To a
stirred solution of 2,2-bis[(2E)-2-carboxy-3-phenylprop-2-en-1-yl]indan-1-
one (4a obtained as above) (0.5 mM, 0.226 g) in dry CH2Cl2 (5 mL) was
added triflouroacetic anhydride (TFAA) (1 mM, 0.21 g). After stirring for
1.5 h at room temperature under N2 atmosphere, the reaction mixture was
diluted with water (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layer was dried over anhydrous Na2SO4. Solvent was
evaporated, and the crude solid thus obtained was purified by crystallization
[ethyl acetate/hexanes (2:3)] to provide 0.20 g (92%) of propellano-
bislactone (5a) as a crystalline solid.
for 1876 independent reflections with I g 2σ(I) to R ) 0.0528, wR2
0.1324, GOF ) 1.090
)
(10) It looks that both the allylic CH2 protons (four protons) (at C-10
and C-17) appear as AB part of ABX system (doublet of AB quartet, i.e.,
two dd) and the downfield doublet (of this system) is merged with singlet
at δ 3.02 of benzylic CH2 protons (at C-8). This is confirmed by the very
clear appearance of AB quartet for both the allylic CH2 protons (four
protons) (at C-10 and C-17) when the 1H NMR spectrum was recorded in
the presence of the shift reagent Eu(fod)3.
Org. Lett., Vol. 3, No. 23, 2001
3621

propellanes using acetates of the Baylis-Hillman adducts,
thus demonstrating the efficacy of Baylis-Hillman chemistry
in synthetic organic chemistry.
University of Hyderabad, funded by DST (New Delhi). We
thank Dr. T. P. Radhakrishnan for helpful discussions
regarding X-ray crystal structure.
Acknowledgment. We thank DST (New Delhi) for
funding this project. We thank the UGC (New Delhi) for
Special Assistance Program in organic chemistry in the-
School of Chemistry, University of Hyderabad. T.S.N. thanks
UGC (New Delhi) for his research fellowship. We thank the
National Single Crystal X-ray facility, School of Chemistry,
Supporting Information Available: Melting points, IR,
1H and 13C NMR spectral data, and 13C NMR spectra of all
propellano-bislactones (5a-g, 9a). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL016469W
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Org. Lett., Vol. 3, No. 23, 2001