Synthesis of novel chiral spirodione, (6R,7R)-7-phenyl-1-oxaspiro[5.5]undec-3-ene-2,5-dione: Application to the asymmetric Diels-Alder reaction with high π-facial selectivity

Article abstract of DOI:10.1016/S0040-4039(03)01176-6

The synthesis of the title spirodione, a new class of auxiliary based chiral synthon using (-)-trans-2-phenylcyclohexanol and its application to the asymmetric Diels-Alder reaction are described. Methodology for detachment of the chiral auxiliary from the cycloadduct has been developed.

Full text of DOI:10.1016/S0040-4039(03)01176-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5015–5017
Synthesis of novel chiral spirodione,
(6R,7R)-7-phenyl-1-oxaspiro[5.5]undec-3-ene-2,5-dione:
application to the asymmetric Diels–Alder reaction with high
p-facial selectivityꢀ
SubbaRao V. Kandula,a Vedavati G. Puranikb and Pradeep Kumara,*
aDivision of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
bDivision of Physical Chemistry, National Chemical Laboratory, Pune 411008, India
Received 14 January 2003; revised 2 May 2003; accepted 9 May 2003
Abstract—The synthesis of the title spirodione, a new class of auxiliary based chiral synthon using (−)-trans-2-phenylcyclohexanol
and its application to the asymmetric Diels–Alder reaction are described. Methodology for detachment of the chiral auxiliary from
the cycloadduct has been developed. © 2003 Elsevier Science Ltd. All rights reserved.
Asymmetric transformations based on a chiral auxiliary
are highly useful and versatile because of the reliable
prediction of stereochemistry that is offered in many
cases.1 The last two decades have witnessed a tremen-
dous upsurge of interest in asymmetric synthesis due to
various emerging theories, e.g. the Cieplak effect,2
nucleophilic and electrophilic surface theory,3 electro-
static interactions,4 s–p interactions,5 FMO theory of
stereoselection,6 theory of steric consideration7 and
steric control of diastereoselection.8 Chiral auxiliaries
such as menthol, menthone, camphor, etc., have been
used extensively for asymmetric synthesis by attaching
an active functional group. The attachment of a func-
tional group to the chiral auxiliary is normally through
an ester, ether or amide linkage. Herein we report the
synthesis of the title auxiliary having a carbonꢀcarbon
Scheme 1. Reagents and conditions: (i) Na2Cr2O7, H2O, 30
bond derived from trans-2-phenylcyclohexanol and its
min, 75%; (ii) Furan, n-BuLi, 6 h, −10°C to rt, 93%; (iii)
mCPBA, dry DCM, 10°C, 4 h, 74%; (iv) Jones’ reagent,
acetone, rt, 30 min, 95%.
successful application to the preparation of enantiomer-
ically pure Diels–Alder products.
The synthesis of the chiral spirodione was achieved as
shown in Scheme 1. 2-Phenylcyclohexanol 1 required
for the synthesis of the chiral spirodione was prepared
either by enzymatic resolution of 2-phenylcyclohexanol9
or by the Sharpless asymmetric dihydroxylation of 2-
phenylcyclohexene10 followed by the selective
hydrogenolysis of the benzylic alcohol with Raney
nickel. (−)-2-Phenylcyclohexanone 2 obtained easily
from 1, was condensed with 2-furyllithium in a
stereoselective manner to furnish the trans-1-(2-furyl)-2-
phenyl-cyclohexanol 3 in 93% yield. Compound 3 was
subjected to oxidative cyclisation by treatment with
m-chloroperoxybenzoic acid, a stereospecific oxidation
rearrangement sequence11 on the furan nucleus, ulti-
mately leading to pyranone derivative 4 which on sub-
sequent treatment with Jones’ reagent afforded the
spirodione 512 as a single diastereomer in excellent yield
ꢀ NCL Communication No. 6640.
* Corresponding author. Tel.: +91-20-5893300 ext. 2050; fax: +91-20-
5893614; e-mail: tripathi@dalton.ncl.res.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01176-6

5016
S. V. Kandula et al. / Tetrahedron Letters 44 (2003) 5015–5017
(Scheme 1). The configuration of 5 was determined as
(6R,7R)-7-phenyl-1-oxaspiro[5.5]undec-3-ene-2,5-dione
based on single-crystal X-ray analysis13 (Fig. 1). The
phenyl group was found syn to the CꢀO bond of the
oxaspirosystem.
The chiral spirodione 5 can exhibit two different facial
selectivities as reported for a similar kind of skeleton.14
Thus, reagents can approach from the ‘a’ side cis to the
phenyl group or from the ‘b’ side opposite to the
phenyl group, as shown in Figure 2.
By taking advantage of the diastereotopic face differ-
ences in 5, we have examined the Diels–Alder reaction
with a view to preparing an optically active skeleton.
The approach of the diene is based on the chiral
auxiliary 5, which is expected to undergo p-face selec-
tive cycloaddition with a variety of dienes. Thus, the
Diels–Alder reaction between dienophile 5 and dienes
such as cyclopentadiene 6a; 2,3-dimethyl-1,3-butadiene
6b; 2-methyl-1,3-pentadiene 6c; in the presence of
diethylaluminium chloride as Lewis acid gave the
cycloadducts 7a–c,15 respectively, as single diastereo-
mers in 92–94% yields (Scheme 2). Diastereoselectivity
was determined on the basis of 13C NMR spec-
troscopy.15
Scheme 2.
Thus, remarkable stereofacial differentiation, 100%
preference for ‘ b’ side to ‘a’ side as depicted in Figure
2 in the Diels–Alder reaction was observed. In contrast
to the literature reports,14c,16 the Diels–Alder reaction
with new chiral spiroskeleton 5 proceeded with high
stereoselectivity but with complete reverse stereofacial
selectivity. The reason for this unexpected reactivity
pattern may be that the approach of the reagent, i.e.
diene from side ‘a’ would cause appreciable steric hin-
drance between the phenyl group and diene, hence the
attack of the reagent occurs preferentially from the ‘b’
side.
In order to obtain the optically pure Diels–Alder
product, we next attempted the detachment of the
chiral auxiliary from the adduct 7a. A variety of meth-
ods employed for the detachment of the chiral auxiliary
such as Bayer–Villiger oxidation followed by hydroly-
sis, photochemical degradation and basic hydrolysis
followed by oxidation were unsuccessful. However,
when 7a was treated with lithium aluminium hydride in
refluxing THF, it gave triol, 8 which on subsequent
oxidative cleavage by lead tetraacetate afforded the
optically pure 2-phenyl cyclohexanone 2 and lactol 9 as
a single enantiomer (Scheme 3).17
In conclusion, the synthesis of a new chiral spiro skele-
ton has been achieved. The efficient application of this
Figure 1. ORTEP diagram of 5; thermal ellipsoids are drawn
at 50% probability.
Scheme 3. Reagents and conditions: (i) LiAlH4, THF, reflux, 3
h, 65%; (ii) Pb(OAc)4, benzene, 0°C, 30 min, 64%.
Figure 2.

S. V. Kandula et al. / Tetrahedron Letters 44 (2003) 5015–5017
5017
chiral auxiliary to a highly versatile Diels–Alder reac-
tion has been demonstrated. We are continuing to
explore the synthetic utility of this novel chiral auxiliary
for a variety of optically active compounds.
1470, 1385, 1330, 1310. 1H NMR (CDCl3, 200 MHz):
1.45–1.65 (m, 1H), 1.68–1.80 (m, 2H), 1.85–2.10 (m, 4H),
2.12–2.22 (dd, J=16, 4 Hz, 1H), 3.10–3.20 (dd, J=16, 4
Hz, 1H), 6.20–6.27 (d, J=16 Hz, 1H), 6.35–6.45 (d,
J=16 Hz, 1H), 7.05–7.15 (m, 2H), 7.17–7.29 (m, 3H). 13
C
NMR (CDCl3, 50 MHz): l 196.31, 160.57, 139.46,
137.20, 134.39, 128.96, 128.79, 127.73, 91.28, 51.46, 35.80,
26.82, 25.51, 20.02. MS m/z: 256 (M+, 14%), 212, 165,
139, 131, 126, 117, 104, 91, 82. Anal. calcd for C16H16O3
(256.29): C, 74.98; H, 6.29. Found: C, 75.13; H, 6.25%.
13. (a) Single crystals were grown by slow evaporation of a
solution in ethyl acetate/pet. ether. Colourless thin
needles of approximate size 0.425×0.210×0.085 mm, were
used for data collection on Bruker SMART APEX CCD
(CCDC Ref. No. 197048) diffractometer using Mo Ka
radiation. C16H16O3; M.wt=256.29. Crystals belong to
Acknowledgements
SubbaRao thanks CSIR, New Delhi for financial assis-
tance. We are grateful to Dr. M. K. Gurjar for his
support and encouragement.
References
monoclinic space group P21/c, a=10.637 (1), b=7.922
1. Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29,
1320–1367.
2. (a) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540–
4552; (b) Cieplak, A. S.; Tait, B. D.; Johnson, C. R. J.
Am. Chem. Soc. 1989, 111, 8447–8462.
3. (a) Kahn, S. D.; Pau, C. F.; Overman, L. E.; Hehre, W.
J. J. Am. Chem. Soc. 1986, 108, 7381–7396; (b) Kahn, S.
D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 663–666;
(c) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman, L.
E. J. Am. Chem. Soc. 1988, 110, 4625–4633.
4. (a) Ganguly, B.; Chandrasekhar, J.; Khan, F. A.; Mehta,
G. J. Org. Chem. 1993, 58, 1734–1739; (b) Paquette, L.
A.; Green, K. E.; Gleiter, R.; Schafer, W.; Gallucci, J. I.;
Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 1993,
115, 8780–8787.
5. (a) Gleiter, R.; Paquette, L. A. Acc. Chem. Res. 1983, 16,
328; (b) Paquette, L. A.; Green, K. E.; Gleiter, R.;
Schafer, W.; Gallucci, J. C. J. Am. Chem. Soc. 1984, 106,
8232–8240.
6. (a) Fujimoto, H. C.; Fukui, K. Tetrahedron Lett. 1966, 7,
5551–5554; (b) Inagaki, S.; Fujimoto, H.; Fukui, K. J.
Am. Chem. Soc. 1976, 98, 4054–4061.
3
,
,
(1), c=15.781 (2) A, i=97.200 (2)°, V=1319.4(3) A ,
Z=4, Dcalcd=1.290 mg m−3, v(Mo Ka) =0.088 mm−1
,
T=293(2) K, 7552 reflections measured, 2994 unique
[I>2|(I)], R value 0.0593, wR2=0.1564. All the data were
corrected for Lorentzian, polarisation and absorption
effects. SHELX-97 (SHELXTL)13b was used for structure
solution and full matrix least-squares refinement on F2.
Hydrogen atoms were included in the refinement as per
the riding model; (b) Sheldrick, G. M., SHELX-97 pro-
gram for crystal structure solution and refinement, Uni-
versity of Go¨ttingen, Germany, 1997.
14. (a) Seebach, D.; Zimmermann, D. J. Helv. Chim. Acta
1986, 69, 1147–1152; (b) Gautschi, M.; Seebach, D.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1083–1085; (c)
Demuth, M.; Palomer, A.; Sluma, H. D.; Dey, A. K.;
Kruger, C.; Tsay, Y. H. Angew. Chem., Int. Ed. Engl.
1986, 25, 1117–1119.
15. Spectral data: 7a: Yield: 90%; [h]2D5 +16.6 (c 11, CHCl3);
IR (neat), cm−1: 1750, 1710, 1455, 1250. 1H NMR (200
MHz) l: 0.98–1.08 (m, 1H), 1.22–1.47 (m, 2H), 1.55–1.73
(m, 4H), 1.75–2.05 (m, 4H), 2.12–2.25 (m, 1H), 2.82–2.95
(dd, J=16, 4 Hz, 1H), 3.26–3.40 (m, 2H), 6.00–6.10 (m,
1H), 6.14–6.22 (m, 1H), 7.07–7.18 (m, 2H), 7.21–7.35 (m,
3H). 13C NMR (CDCl3, 50 MHz): 208.83, 169.81, 139.22,
136.48, 129.52, 128.82, 127.91, 91.51, 52.01, 48.90, 48.37,
42.27, 33.91, 26.76, 25.38, 19.78. MS m/z 322 (M+, 5%),
256 (29), 212 (85), 165 (20), 148 (33), 139 (71), 130 (100),
120 (71), 91 (98). Anal. calcd for C21H22O3 (322.39): C,
78.23; H, 6.88. Found: C, 78.31; H, 6.78%.
7. Brown, H. C.; Kawakami, J. H.; Liu, K. T. J. Am. Chem.
Soc. 1973, 95, 2209–2216.
8. (a) Houk, K. N.; Paddon Row, M. N.; Rondan, N. G.;
Wu, Y. D.; Brown, F. K.; Spelimeyer, D. C.; Metz, J. T.;
Li, Y.; Loncharich, R. J. Science 1986, 231, 1108–1116;
(b) Houk, K. N.; Brown, F. K. J. Am. Chem. Soc. 1985,
107, 1971–1978; (c) Houk, K. N.; Wu, Y. J. Am. Chem.
Soc. 1987, 109, 908–910.
16. (a) Sato, M.; Takayama, K.; Furaya, T.; Inukai, N.;
Kaneko, C. Chem. Pharm. Bull. 1987, 3974; (b) Feringa,
B. L.; De Jong, J. C. J. Org. Chem. 1988, 53, 1125–1127.
17. Spectral data: 9: Yield: 64%, [h]2D5: −23.3 (c 1.0, CHCl3);
IR (CHCl3), cm−1: 3390, 2900, 2870, 1251, 1085, 1045,
995. 1H NMR (CDCl3, 200 MHz): 1.30–1.45 (m, 2H),
2.80–3.02 (m, 4H), 3.38–3.45 (dd, J=8, 4 Hz, 2H), 3.90–
4.00 (m, 1H), 4.95 (s, 1H), 6.02–6.09 (m, 1H), 6.14–6.20
(m, 1H). 13C NMR (CDCl3, 50 MHz): 136.29, 135.51,
88.23, 65.06, 55.45, 46.91, 44.30, 44.20, 43.71. MS m/z:
152 (M+, 2%), 135, 122, 105, 91, 66.
9. (a) White, J. K.; Chen, H. H.; Lawrence, R. M. J. Org.
Chem. 1985, 50, 4663–4664; (b) Basavaiah, D.; Krishna,
P. R.; Bharathi, T. K. Tetrahedron Lett. 1990, 31, 4347–
4348.
10. King, S. B.; Sharpless, K. B. Tetrahedron Lett. 1994, 35,
5611–5612.
11. Georgiadis, M. P.; Sekouras, A.; Kotretrou, S. I.;
Horoutouniam, S. A.; Polissiou, M. G. Synthesis 1991,
929–932.
12. Spectral data: 5: Yield: 95%, mp: 97°C [h]2D5: +74.9 (c 10,
CHCl3), IR (neat), cm−1: 2910, 2860, 1735, 1690, 1625,